U.S. patent application number 13/797106 was filed with the patent office on 2013-10-10 for ncrna and uses thereof.
This patent application is currently assigned to The Regents of the University of Michigan. The applicant listed for this patent is Arul Chinnaiyan, Matthew Iyer, John Prensner. Invention is credited to Arul Chinnaiyan, Matthew Iyer, John Prensner.
Application Number | 20130267443 13/797106 |
Document ID | / |
Family ID | 49292787 |
Filed Date | 2013-10-10 |
United States Patent
Application |
20130267443 |
Kind Code |
A1 |
Chinnaiyan; Arul ; et
al. |
October 10, 2013 |
ncRNA AND USES THEREOF
Abstract
The present invention relates to compositions and methods for
cancer diagnosis, research and therapy, including but not limited
to, cancer markers. In particular, the present invention relates to
ncRNAs as diagnostic markers and clinical targets for prostate,
lung, breast and pancreatic cancer.
Inventors: |
Chinnaiyan; Arul; (Plymouth,
MI) ; Prensner; John; (Ann Arbor, MI) ; Iyer;
Matthew; (Ann Arbor, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chinnaiyan; Arul
Prensner; John
Iyer; Matthew |
Plymouth
Ann Arbor
Ann Arbor |
MI
MI
MI |
US
US
US |
|
|
Assignee: |
The Regents of the University of
Michigan
Ann Arbor
MI
|
Family ID: |
49292787 |
Appl. No.: |
13/797106 |
Filed: |
March 12, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13299000 |
Nov 17, 2011 |
|
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13797106 |
|
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61415490 |
Nov 19, 2010 |
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Current U.S.
Class: |
506/39 |
Current CPC
Class: |
C12Q 2600/112 20130101;
C12Q 2600/118 20130101; C12Q 2600/158 20130101; C12Q 2600/136
20130101; C12Q 2600/106 20130101; C12Q 1/6886 20130101; A61K
31/4184 20130101 |
Class at
Publication: |
506/39 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under
CA111275 awarded by the National Institutes of Health and
@81XWH-08-1-0031 and @81XWH-11-1-0520 awarded by the U.S. Army
Medical Research and Materiel Command. The government has certain
rights in the invention.
Claims
1.-272. (canceled)
273. A system for analyzing a cancer, comprising: a. a probe set
comprising a plurality of probes, wherein the plurality of probes
comprises a sequence that hybridizes to at least a portion of one
or more target molecules selected from the group comprising PCAT,
SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,
TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; and b. a computer
model or algorithm for analyzing an expression level and/or
expression profile of a target molecule hybridized to the probe in
a sample from a subject suffering from a cancer.
274. The system claim 273, wherein PCAT is selected from the group
comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8,
PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16,
PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23, PCAT24,
PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,
PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40,
PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48,
PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,
PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64,
PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72,
PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80,
PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88,
PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95, PCAT96,
PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,
PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110,
PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117,
PCAT118, PCAT119, PCAT120, and PCAT121.
275. The system of claim 273, further comprising an electronic
memory for capturing and storing an expression profile.
276. The system of claim 273, further comprising a
computer-processing device, optionally connected to a computer
network.
277. The system of claim 276, further comprising a software module
executed by the computer-processing device to analyze an expression
profile.
278. The system of claim 276, further comprising a software module
executed by the computer-processing device to compare the
expression profile to a standard or control.
279. The system of claim 276, further comprising a software module
executed by the computer-processing device to determine the
expression level of the target.
280. The system of claim 276, further comprising a software module
executed by the computer-processing device to transmit an analysis
of the expression profile to the subject or a medical professional
treating the subject.
281. The system of claim 276, further comprising a software module
executed by the computer-processing device to transmit a diagnosis
or prognosis to the subject or a medical professional treating the
subject.
282. The system of claim 273, further comprising a machine to
isolate the target or the probe from the sample, a machine to
sequence the target or the probe, and/or a machine to amplify the
target or the probe.
283. The system of claim 273, wherein the plurality of probes
comprises a sequence that hybridizes to at least a portion of two
or more target molecules selected from the group comprising PCAT,
SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,
TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9.
284. The system of claim 273, wherein the cancer is selected from
the group comprising prostate, lung, breast, and pancreatic
cancer.
285. The system of claim 273, wherein the plurality of probes
comprises a sequence that hybridizes to at least a portion of one
or more target molecules selected from the group comprising and SEQ
ID NOs: 1-9, PCAT1, PCAT14, PCAT43, PCAT 109, and SChLAP-1.
286. The system of claim 285, wherein the cancer is a prostate
cancer.
287. The system of claim 273, wherein the plurality of probes
comprises a sequence that hybridizes to at least a portion of one
or more target molecules selected from the group comprising M41 and
ENST-75.
288. The system of claim 287, wherein the cancer is a lung
cancer.
289. The system of claim 273, wherein the plurality of probes
comprises a sequence that hybridizes to at least a portion of one
or more target molecules selected from the group comprising
TU0011194, TU0019356 and TU0024146.
290. The system of claim 288, wherein the cancer is a breast cancer
or prostate.
291. The system of claim 273, wherein the plurality of probes is
attached to one or more solid supports.
292. The system of claim 291, wherein the one or more solid
supports is a bead, array, microarray, well, plate, chip, or a
combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 13/299,000 filed Nov. 17, 2011, which claims
priority to U.S. Provisional Application No. 61/415,490, filed Nov.
19, 2010, each of which are herein incorporated by referenced in
its entirety.
FIELD OF THE INVENTION
[0003] The present invention relates to compositions and methods
for cancer diagnosis, research and therapy, including but not
limited to, cancer markers. In particular, the present invention
relates to ncRNAs as diagnostic markers and clinical targets for
prostate, lung, breast and pancreatic cancer.
BACKGROUND OF THE INVENTION
[0004] A central aim in cancer research is to identify altered
genes that are causally implicated in oncogenesis. Several types of
somatic mutations have been identified including base
substitutions, insertions, deletions, translocations, and
chromosomal gains and losses, all of which result in altered
activity of an oncogene or tumor suppressor gene. First
hypothesized in the early 1900's, there is now compelling evidence
for a causal role for chromosomal rearrangements in cancer (Rowley,
Nat Rev Cancer 1: 245 (2001)). Recurrent chromosomal aberrations
were thought to be primarily characteristic of leukemias,
lymphomas, and sarcomas. Epithelial tumors (carcinomas), which are
much more common and contribute to a relatively large fraction of
the morbidity and mortality associated with human cancer, comprise
less than 1% of the known, disease-specific chromosomal
rearrangements (Mitelman, Mutat Res 462: 247 (2000)). While
hematological malignancies are often characterized by balanced,
disease-specific chromosomal rearrangements, most solid tumors have
a plethora of non-specific chromosomal aberrations. It is thought
that the karyotypic complexity of solid tumors is due to secondary
alterations acquired through cancer evolution or progression.
[0005] Two primary mechanisms of chromosomal rearrangements have
been described. In one mechanism, promoter/enhancer elements of one
gene are rearranged adjacent to a proto-oncogene, thus causing
altered expression of an oncogenic protein. This type of
translocation is exemplified by the apposition of immunoglobulin
(IG) and T-cell receptor (TCR) genes to MYC leading to activation
of this oncogene in B- and T-cell malignancies, respectively
(Rabbitts, Nature 372: 143 (1994)). In the second mechanism,
rearrangement results in the fusion of two genes, which produces a
fusion protein that may have a new function or altered activity.
The prototypic example of this translocation is the BCR-ABL gene
fusion in chronic myelogenous leukemia (CML) (Rowley, Nature 243:
290 (1973); de Klein et al., Nature 300: 765 (1982)). Importantly,
this finding led to the rational development of imatinib mesylate
(Gleevec), which successfully targets the BCR-ABL kinase (Deininger
et al., Blood 105: 2640 (2005)). Thus, diagnostic methods that
specifically identify epithelial tumors are needed.
SUMMARY OF THE INVENTION
[0006] The present invention relates to compositions and methods
for cancer diagnosis, research and therapy, including but not
limited to, cancer markers. In particular, the present invention
relates to ncRNAs as diagnostic markers and clinical targets for
cancer (e.g., prostate, lung, breast and pancreatic cancer).
[0007] Embodiments of the present invention provide compositions,
kits, and methods useful in the detection and screening of a
cancer. Experiments conducted during the course of development of
embodiments of the present invention identified upreguation of one
or more non-coding RNAs in cancer. Some embodiments of the present
invention provide compositions and methods for detecting expression
levels of such ncRNAs. Identification of ncRNAs finds use in
screening, diagnostic and research uses.
[0008] For example, in some embodiments, the present invention
provides a method of screening for the presence of a cancer in a
subject, comprising contacting a biological sample from a subject
with a reagent for detecting the level of expression of one or more
non-coding RNAs (ncRNA); and detecting the level of expression of
the ncRNA in the sample, wherein an increased level of expression
of the ncRNA in the sample is indicative of a cancer in the
subject. In some embodiments, the cancer is a prostate cancer. In
some instances, the increased level of expression of the ncRNA in
the sample is relative to the level of ncRNA in a control sample.
The control sample may comprise one or more normal cells. In some
instances, the normal cells are normal prostate cells. In other
instances, the increased level of expression of the ncRNA in the
sample is relative to the level of expression of the ncRNA in a
sample from a prior time point. Alternatively, the increased level
of expression of the ncRNA in the sample is relative to a
pre-established threshold level. In some embodiments, the ncRNAs
are described by SEQ ID NOs: 1-9. In some embodiments, the
non-coding RNAs comprise one or more PCAT transcripts. In some
embodiments, the non-coding RNAs are selected from the group
comprising PCAT1, PCAT14, PCAT43 and PCAT 109. In some embodiments,
the sample is tissue, blood, plasma, serum, urine, urine
supernatant, urine cell pellet, semen, prostatic secretions or
prostate cells. In some instances, detecting the level of
expression of the ncRNA comprises one or more in vitro assays. In
some embodiments, the detection is carried out utilizing a
sequencing technique, a nucleic acid hybridization technique, a
nucleic acid amplification technique, or an immunoassay. However,
the invention is not limited to the technique employed. In some
embodiments, the nucleic acid amplification technique is polymerase
chain reaction, reverse transcription polymerase chain reaction,
transcription-mediated amplification, ligase chain reaction, strand
displacement amplification or nucleic acid sequence based
amplification. In some embodiments, the prostate cancer is
localized prostate cancer or metastatic prostate cancer. In some
embodiments, the reagent is a pair of amplification
oligonucleotides or an oligonucleotide probe.
[0009] Additional embodiments provide a method of screening for the
presence of a cancer in a subject, comprising contacting a
biological sample from a subject with a reagent for detecting the
level of expression of two or more (e.g., 10 or more, 25 or more,
50 or more, 100 or more or all 121) non-coding RNAs (ncRNA); and
detecting the level of expression of the ncRNA in the sample,
wherein an increased level of expression of the ncRNA in the sample
is indicative of cancer in the subject. In some embodiments, the
cancer is a prostate cancer. In some instances, the increased level
of expression of the ncRNA in the sample is relative to the level
of ncRNA in a control sample. The control sample may comprise one
or more normal cells. In some instances, the normal cells are
normal prostate cells. In other instances, the increased level of
expression of the ncRNA in the sample is relative to the level of
expression of the ncRNA in a sample from a prior time point.
Alternatively, the increased level of expression of the ncRNA in
the sample is relative to a pre-established threshold level. In
some embodiments, at least one of the two or more ncRNAs are
selected from a group comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5,
PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14,
PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22,
PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30,
PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,
PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46,
PCAT47, PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54,
PCAT55, PCAT56, PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62,
PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70,
PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78,
PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86,
PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94,
PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102,
PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109,
PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,
PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121. In some
embodiments, the two or more ncRNAs are selected from the group
comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8,
PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16,
PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23, PCAT24,
PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,
PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40,
PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48,
PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,
PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64,
PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72,
PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80,
PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88,
PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95, PCAT96,
PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,
PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110,
PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117,
PCAT118, PCAT119, PCAT120, and PCAT121. In some instances,
detecting the level of expression of the ncRNA comprises one or
more in vitro assays.
[0010] Further embodiments of the present invention provide an
array, comprising reagents for detecting the level of expression of
two or more (e.g., 10 or more, 25 or more, 50 or more, 100 or more
or all 121) non-coding RNAs (ncRNA) selected from, for example,
PCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8, PCAT9,
PCAT10, PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16, PCAT17,
PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23, PCAT24, PCAT25,
PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32, PCAT33,
PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40, PCAT41,
PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48, PCAT49,
PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56, PCAT57,
PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64, PCAT65,
PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72, PCAT73,
PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80, PCAT81,
PCAT82, PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88, PCAT89,
PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95, PCAT96, PCAT97,
PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103, PCAT104,
PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110, PCAT111,
PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117, PCAT118,
PCAT119, PCAT120, or PCAT121. In some embodiments, the reagent is a
pair of amplification oligonucleotides or an oligonucleotide
probe.
[0011] In some embodiments, the present invention provides a method
for screening for the presence of a cancer in a subject, comprising
contacting a biological sample from a subject with a reagent for
detecting the level of expression of one or more non-coding RNAs;
and detecting the level of expression of the ncRNA in the sample,
wherein an increased level of expression of the ncRNA in the sample
is indicative of cancer in the subject. In some instances, the
cancer is a lung cancer. In some instances, the increased level of
expression of the ncRNA in the sample is relative to the level of
ncRNA in a control sample. The control sample may comprise one or
more normal cells. In some instances, the normal cells are normal
lung cells. In other instances, the increased level of expression
of the ncRNA in the sample is relative to the level of expression
of the ncRNA in a sample from a prior time point. Alternatively,
the increased level of expression of the ncRNA in the sample is
relative to a pre-established threshold level. In some instances,
the one or more non-coding RNAs are selected from the group
comprising M41 and ENST-75. In some instances, detecting the level
of expression of the ncRNA comprises one or more in vitro
assays.
[0012] In some embodiments, the present invention provides a method
for screening for the presence of a cancer in a subject, comprising
contacting a biological sample from a subject with a reagent for
detecting the level of expression of one or more non-coding RNAs;
and detecting the level of expression of the ncRNA in the sample,
wherein an increased level of expression of the ncRNA in the sample
is indicative of cancer in the subject. In some instances, the
cancer is a breast cancer. In some instances, the increased level
of expression of the ncRNA in the sample is relative to the level
of ncRNA in a control sample. The control sample may comprise one
or more normal cells. In some instances, the normal cells are
normal breast cells. In other instances, the increased level of
expression of the ncRNA in the sample is relative to the level of
expression of the ncRNA in a sample from a prior time point.
Alternatively, the increased level of expression of the ncRNA in
the sample is relative to a pre-established threshold level. In
some instances, the one or more ncRNAs are selected from the group
comprising TU0011194, TU0019356 and TU0024146. In some instances,
detecting the level of expression of the ncRNA comprises one or
more in vitro assays.
[0013] In some embodiments, the present invention provides a method
for screening for the presence of cancer in a subject, comprising
contacting a biological sample from a subject with a reagent for
detecting the level of expression of one or more non-coding RNAs;
and detecting the level of expression of the ncRNA in the sample,
wherein an increased level of expression of the ncRNA in the sample
is indicative of cancer in the subject. In some instances, the
cancer is a pancreatic cancer. In some instances, the increased
level of expression of the ncRNA in the sample is relative to the
level of ncRNA in a control sample. The control sample may comprise
one or more normal cells. In some instances, the normal cells are
normal pancreatic cells. In other instances, the increased level of
expression of the ncRNA in the sample is relative to the level of
expression of the ncRNA in a sample from a prior time point.
Alternatively, the increased level of expression of the ncRNA in
the sample is relative to a pre-established threshold level. In
some instances, the one or more ncRNAs are selected from the group
comprising TU0011194, TU0019356 and TU0024146. In some instances,
detecting the level of expression of the ncRNA comprises one or
more in vitro assays.
[0014] In still further embodiments, the present invention provides
a method of screening for the presence of a cancer in a subject,
comprising (a) contacting a biological sample from a subject with a
gene expression detection assay, wherein the gene expression
detection assay comprises a gene expression informative reagent for
identification of the level of expression of SChLAP-1; (b)
detecting the level of expression of SChLAP-1 in the sample; and
(c) diagnosing cancer in the subject when an increased level of
expression of SChLAP-1 in the sample is detected. In some
instances, the cancer is a prostate cancer. In some instances, the
increased level of expression of SChLAP-1 in the sample is relative
to the level of SChLAP-1 in a control sample. The control sample
may comprise one or more normal cells. In some instances, the
normal cells are normal prostate cells. In other instances, the
increased level of expression of SChLAP-1 in the sample is relative
to the level of expression of SChLAP-1 in a sample from a prior
time point. Alternatively, the increased level of expression of
SChLAP-1 in the sample is relative to a pre-established threshold
level. In some instances, detecting the level of expression of
SChLAP-1 comprises one or more in vitro assays. In some instances,
the gene expression detection assay further comprises a gene
expression informative reagent for identification of the level of
expression of one or more ncRNAs.
[0015] In additional embodiments, the present invention provides a
method of identifying subjects at risk of cancer metastatis,
comprising (a) contacting a biological sample from a subject with a
gene expression detection assay, wherein the gene expression
detection assay comprises a gene expression informative reagent for
identification of the level of expression of SChLAP-1; (b)
detecting the level of expression of SChLAP-1 in the sample using
an in vitro assay; and (c)
[0016] identifying subjects at risk of cancer metastasis when an
increased level of expression of SChLAP-1 in the sample is
detected. In some embodiments, the subject is at increased risk of
lethal prostate cancer when an increased level of expression of
SChLAP-1 in the sample is detected. In some instances, the cancer
is a prostate cancer. In some instances, the increased level of
expression of SChLAP-1 in the sample is relative to the level of
SChLAP-1 in a control sample. The control sample may comprise one
or more normal cells. In some instances, the normal cells are
normal prostate cells. In other instances, the increased level of
expression of SChLAP-1 in the sample is relative to the level of
expression of SChLAP-1 in a sample from a prior time point.
Alternatively, the increased level of expression of SChLAP-1 in the
sample is relative to a pre-established threshold level. In some
instances, detecting the level of expression of SChLAP-1 comprises
one or more in vitro assays. In some instances, the gene expression
detection assay further comprises a gene expression informative
reagent for identification of the level of expression of one or
more ncRNAs.
[0017] Disclosed herein may be methods, systems, compositions and
kits for analyzing, diagnosing, prognosing, monitoring, and/or
treating a cancer. Such systems may comprise (a) a probe set may
comprise a plurality of probes, wherein the plurality of probes may
comprise a sequence that hybridizes to at least a portion of one or
more target molecules selected from the group may comprise PCAT,
SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,
TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; and (b) a computer
model or algorithm for analyzing an expression level and/or
expression profile of a target molecule hybridized to the probe in
a sample from a subject suffering from a cancer. The PCAT may be
selected from the group may comprise PCAT1, PCAT2, PCAT3, PCAT4,
PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13,
PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21,
PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,
PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37,
PCAT38, PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45,
PCAT46, PCAT47, PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53,
PCAT54, PCAT55, PCAT56, PCAT57, PCAT58, PCAT59, PCAT60, PCAT61,
PCAT62, PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68, PCAT69,
PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77,
PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85,
PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93,
PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101,
PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,
PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115,
PCAT116, PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121.
[0018] The system may further comprise an electronic memory for
capturing and storing an expression profile.
[0019] The system may further comprise a computer-processing
device, optionally connected to a computer network.
[0020] The system may further comprise a software module executed
by the computer-processing device to analyze an expression
profile.
[0021] The system may further comprise a software module executed
by the computer-processing device to compare the expression profile
to a standard or control.
[0022] The system may further comprise a software module executed
by the computer-processing device to determine the expression level
of the target.
[0023] The system may further comprise a machine to isolate the
target molecule or the probe from the sample.
[0024] The system may further comprise a machine to sequence the
target molecule or the probe.
[0025] The system may further comprise a machine to amplify the
target molecule or the probe.
[0026] The system may further comprise a label that specifically
binds to the target molecule the probe, or a combination
thereof.
[0027] The system may further comprise a software module executed
by the computer-processing device to transmit an analysis of the
expression profile to the subject or a medical professional
treating the subject.
[0028] The system may further comprise a software module executed
by the computer-processing device to transmit a diagnosis or
prognosis to the subject or a medical professional treating the
subject.
[0029] Further disclosed herein are kits comprising (a) a probe set
may comprise a plurality of probes, wherein the plurality of probes
may comprise a sequence that hybridizes to at least a portion of
one or more target molecules selected from the group may comprise
PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141,
TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9; and (b) a
computer model or algorithm for analyzing an expression level
and/or expression profile of the target molecules in a sample.
[0030] The kit may further comprise a computer model or algorithm
for correlating the expression level or expression profile with
disease state or outcome.
[0031] The kit may further comprise a computer model or algorithm
for designating a treatment modality for the subject.
[0032] The kit may further comprise a computer model or algorithm
for normalizing expression level or expression profile of the
target molecules.
[0033] The kit may further comprise a computer model or algorithm
may comprise a robust multichip average (RMA), probe logarithmic
intensity error estimation (PLIER), non-linear fit (NLFIT)
quantile-based, nonlinear normalization, or a combination
thereof.
[0034] Methods for analyzing a cancer in a subject in need thereof
may comprise (a) obtaining an expression profile from a sample
obtained from the subject, wherein the expression profile comprises
one or more target molecules selected from PCAT, SChLAP-1,
TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861,
M41, ENST-75, and SEQ ID NOs: 1-9; and (b) comparing the expression
profile from the sample to an expression profile of a control or
standard.
[0035] Disclosed herein may be methods, systems, compositions and
kits for diagnosing a cancer. Such methods for diagnosing cancer in
a subject in need thereof may comprise (a) obtaining an expression
profile from a sample obtained from the subject, wherein the
expression profile may comprise one or more target molecules
selected from PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9;
(b) comparing the expression profile from the sample to an
expression profile of a control or standard; and (c) diagnosing a
cancer in the subject if the expression profile of the sample (i)
deviates from the control or standard from a healthy subject or
population of healthy subjects, or (ii) matches the control or
standard from a subject or population of subjects who have or have
had the cancer.
[0036] Disclosed herein may be methods, systems, compositions and
kits for predicting susceptibility to developing cancer. Such
methods for predicting whether a subject may be susceptible to
developing a cancer may comprise (a) obtaining an expression
profile from a sample obtained from the subject, wherein the
expression profile may comprise one or more target molecules
selected from PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9;
(b) comparing the expression profile from the sample to an
expression profile of a control or standard; and (c) predicting the
susceptibility of the subject for developing a cancer based on (i)
the deviation of the expression profile of the sample from a
control or standard derived from a healthy subject or population of
healthy subjects, or (ii) the similarity of the expression profiles
of the sample and a control or standard derived from a subject or
population of subjects who have or have had the cancer.
[0037] Disclosed herein may be methods, systems, compositions and
kits for predicting response to a treatment regimen for cancer.
Such methods for predicting a subject's response to a treatment
regimen for a cancer may comprise: (a) obtaining an expression
profile from a sample obtained from the subject, wherein the
expression profile may comprise one or more target molecules
selected from PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9;
(b) comparing the expression profile from the sample to an
expression profile of a control or standard; and (c) predicting the
subject's response to a treatment regimen based on (i) the
deviation of the expression profile of the sample from a control or
standard derived from a healthy subject or population of healthy
subjects, or (ii) the similarity of the expression profiles of the
sample and a control or standard derived from a subject or
population of subjects who have or have had the cancer.
[0038] Disclosed herein may be methods, systems, compositions and
kits for treating or determining a treatment regimen for cancer.
Such methods treating or determining a treatment regimen for cancer
may comprise: (a) obtaining an expression profile from a sample
obtained from the subject, wherein the expression profile may
comprise one or more target molecules selected from PCAT, SChLAP-1,
TU0011194, TU0019356, TU0024146, TU0009141, TU0062051, TU0021861,
M41, ENST-75, and SEQ ID NOs: 1-9; (b) comparing the expression
profile from the sample to an expression profile of a control or
standard; and (c) treating or determining a treatment regimen for
cancer based on (i) the deviation of the expression profile of the
sample from a control or standard derived from a healthy subject or
population of healthy subjects, or (ii) the similarity of the
expression profiles of the sample and a control or standard derived
from a subject or population of subjects who have or have had the
cancer.
[0039] The method may further comprise a software module executed
by a computer-processing device to compare the expression
profiles.
[0040] The method may further comprise providing diagnostic or
prognostic information to the subject about the cancer based on the
comparison.
[0041] The method may further comprise diagnosing the subject with
a cancer if the expression profile of the sample (a) deviates from
the control or standard from a healthy subject or population of
healthy subjects, or (b) matches the control or standard from a
subject or population of subjects who have or have had the
cancer.
[0042] The method may further comprise predicting the
susceptibility of the subject for developing a cancer based on (a)
the deviation of the expression profile of the sample from a
control or standard derived from a healthy subject or population of
healthy subjects, or (b) the similarity of the expression profiles
of the sample and a control or standard derived from a subject or
population of subjects who have or have had the cancer.
[0043] The method may further comprise prescribing a treatment
regimen based on (a) the deviation of the expression profile of the
sample from a control or standard derived from a healthy subject or
population of healthy subjects, or (b) the similarity of the
expression profiles of the sample and a control or standard derived
from a subject or population of subjects who have or have had the
cancer.
[0044] The method may further comprise altering a treatment regimen
prescribed or administered to the subject based on (a) the
deviation of the expression profile of the sample from a control or
standard derived from a healthy subject or population of healthy
subjects, or (b) the similarity of the expression profiles of the
sample and a control or standard derived from a subject or
population of subjects who have or have had the cancer.
[0045] The method may further comprise predicting the subject's
response to a treatment regimen based on (a) the deviation of the
expression profile of the sample from a control or standard derived
from a healthy subject or population of healthy subjects, or (b)
the similarity of the expression profiles of the sample and a
control or standard derived from a subject or population of
subjects who have or have had the cancer.
[0046] The method may further comprise using a machine to isolate
the one or more target molecules, one or more probes, or one or
more probe hybridized target molecules from the sample.
[0047] The method may further comprise contacting the sample with a
label that specifically binds to the target molecule, the probe, or
a combination thereof.
[0048] The method may further comprise contacting the sample with a
label that specifically binds to one or more target molecules.
[0049] The method may further comprise amplifying at least a
portion of the target molecule, the probe, or any combination
thereof.
[0050] The method may further comprise sequencing at least a
portion of the target molecule, the probe, or any combination
thereof.
[0051] Further disclosed herein is a probe set for assessing a
cancer status of a subject may comprise a plurality of probes,
wherein the probes in the probe set may be capable of detecting an
expression level of one or more target molecules selected from the
group may comprise PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9,
wherein The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 40%
accuracy.
[0052] The methods, systems, compositions and kits may comprise a
plurality of probes. The plurality of probes may comprise a
sequence that hybridizes to at least a portion of two or more
target molecules selected from the group may comprise PCAT,
SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,
TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9. The plurality of
probes may comprise a sequence that hybridizes to at least a
portion of three or more target molecules selected from the group
may comprise PCAT, SChLAP-1, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9.
The plurality of probes may comprise a sequence that hybridizes to
at least a portion of four or more target molecules selected from
the group may comprise PCAT, SChLAP-1, TU0011194, TU0019356,
TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ
ID NOs: 1-9. The plurality of probes may comprise a sequence that
hybridizes to at least a portion of five or more target molecules
selected from the group may comprise PCAT, SChLAP-1, TU0011194,
TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, M41,
ENST-75, and SEQ ID NOs: 1-9. The plurality of probes may comprise
a sequence that hybridizes to at least a portion of ten or more
target molecules selected from the group may comprise PCAT,
SChLAP-1, TU0011194, TU0019356, TU0024146, TU0009141, TU0062051,
TU0021861, M41, ENST-75, and SEQ ID NOs: 1-9.
[0053] The plurality of probes may comprise a sequence that
hybridizes to at least a portion of one or more target molecules
selected from the group may comprise and SEQ ID NOs: 1-9. The
plurality of probes may comprise a sequence that hybridizes to at
least a portion of one or more target molecules selected from the
group may comprise PCAT1, PCAT14, PCAT43 and PCAT 109. The
plurality of probes may comprise a sequence that hybridizes to at
least a portion of one or more target molecules may comprise
SChLAP-1. The plurality of probes may comprise a sequence that
hybridizes to at least a portion of one or more target molecules
selected from the group may comprise PCAT1, PCAT2, PCAT3, PCAT4,
PCAT5, PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13,
PCAT14, PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21,
PCAT22, PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29,
PCAT30, PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37,
PCAT38, PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45,
PCAT46, PCAT47, PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53,
PCAT54, PCAT55, PCAT56, PCAT57, PCAT58, PCAT59, PCAT60, PCAT61,
PCAT62, PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68, PCAT69,
PCAT70, PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77,
PCAT78, PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85,
PCAT86, PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93,
PCAT94, PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101,
PCAT102, PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108,
PCAT109, PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115,
PCAT116, PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121. The
cancer may be a prostate cancer.
[0054] The plurality of probes may comprise a sequence that
hybridizes to at least a portion of one or more target molecules
selected from the group may comprise M41 and ENST-75. The cancer
may be a lung cancer.
[0055] The plurality of probes may comprise a sequence that
hybridizes to at least a portion of one or more target molecules
selected from the group may comprise TU0011194, TU0019356 and
TU0024146. The cancer may be a breast cancer.
[0056] The plurality of probes may comprise a sequence that
hybridizes to at least a portion of one or more target molecules
selected from the group may comprise TU0011194, TU0019356 and
TU0024146. The cancer may be a pancreatic cancer.
[0057] The probes may be between about 15 nucleotides and about 500
nucleotides in length. The probes may be between about 15
nucleotides and about 450 nucleotides in length. The probes may be
between about 15 nucleotides and about 400 nucleotides in length.
The probes may be between about 15 nucleotides and about 350
nucleotides in length. The probes may be between about 15
nucleotides and about 300 nucleotides in length. The probes may be
between about 15 nucleotides and about 250 nucleotides in length.
The probes may be between about 15 nucleotides and about 200
nucleotides in length. The probes may be at least 15 nucleotides in
length. The probes may be at least 25 nucleotides in length.
[0058] The cancer may be selected from the group may comprise
prostate, lung, breast, and pancreatic cancer.
[0059] Assessing the cancer status may comprise assessing cancer
recurrence risk. Assessing the cancer status may comprise
determining a treatment modality. Assessing the cancer status may
comprise determining the efficacy of treatment.
[0060] Obtaining an expression profile may comprise hybridizing one
or more probes to the one or more target molecules to produce one
or more probe hybridized target molecules.
[0061] The deviation may be the expression level of one or more
targets from the sample may be greater than the expression level of
one or more targets from a control or standard derived from a
healthy subject or population of healthy subjects. The deviation
may be the expression level of one or more targets from the sample
may be at least about 30% greater than the expression level of one
or more targets from a control or standard derived from a healthy
subject or population of healthy subjects. The deviation may be the
expression level of one or more targets from the sample may be less
than the expression level of one or more targets from a control or
standard derived from a healthy subject or population of healthy
subjects. The deviation may be the expression level of one or more
targets from the sample may be at least about 30% less than the
expression level of one or more targets from a control or standard
derived from a healthy subject or population of healthy
subjects.
[0062] The expression level of the one or more target molecules may
determine the cancer status of the subject with at least 50%
accuracy. The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 60%
accuracy. The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 65%
accuracy. The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 70%
accuracy. The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 75%
accuracy. The expression level of the one or more target molecules
may determine the cancer status of the subject with at least 80%
accuracy.
[0063] The plurality of probes may determine the expression level
of the one or more target molecules with at least about 50%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 60%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 65%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 70%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 75%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 80%
specificity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 85%
specificity.
[0064] The plurality of probes may determine the expression level
of the one or more target molecules with at least about 50%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 60%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 65%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 70%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 75%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 80%
sensitivity. The plurality of probes may determine the expression
level of the one or more target molecules with at least about 85%
sensitivity.
[0065] Additional embodiments are described herein.
DESCRIPTION OF THE FIGURES
[0066] FIG. 1 shows that prostate cancer transcriptome sequencing
reveals dysregulation of exemplary transcripts identified herein.
a. A global overview of transcription in prostate cancer. b. A line
graph showing the cumulative fraction of genes that are expressed
at a given RPKM level. c. Conservation analysis comparing
unannotated transcripts to known genes and intronic controls shows
a low but detectable degree of purifying selection among intergenic
and intronic unannotated transcripts. d-g. Intersection plots
displaying the fraction of unannotated transcripts enriched for
H3K4me2 (d), H3K4me3 (e), Acetyl-H3 (f) or RNA polymerase II (g) at
their transcriptional start site (TSS) using ChIP-Seq and RNA-Seq
data for the VCaP prostate cancer cancer cell line. h. A heatmap
representing differentially expressed transcripts, including novel
unannotated transcripts, in prostate cancer.
[0067] FIG. 2 shows that unannotated intergenic transcripts
differentiate prostate cancer and benign prostate samples. a. A
histogram plotting the genomic distance between an unannotated
ncRNA and the nearest protein-coding gene. b. A Circos plot
displaying the location of annotated transcripts and unannotated
transcripts on Chr15q. c. A heatmap of differentially expressed or
outlier unannotated intergenic transcripts clusters benign samples,
localized tumors, and metastatic cancers by unsupervised clustering
analyses. d. Cancer outlier profile analysis (COPA) outlier
analysis for the prostate cancer transcriptome reveals known
outliers (SPINK1, ERG, and ETV1), as well as numerous unannotated
transcripts.
[0068] FIG. 3 shows validation of tissue-specific prostate
cancer-associated non-coding RNAs. a-c. Quantitative real-time PCR
was performed on a panel of prostate and non-prostate samples to
measure expression levels of three nominated non-coding RNAs
(ncRNAs), PCAT-43, PCAT-109, and PCAT-14, upregulated in prostate
cancer compared to normal prostate tissues. a. PCAT-43 is a 20 kb
ncRNA located 40 kb upstream of PMEPA1 on chr20q13.31. b. PCAT-109,
located in a large, 0.5 Mb gene desert region on chr2q31.3 displays
widespread transcription in prostate tissues, particularly
metastases. c. PCAT-14, a genomic region on chr22q11.23
encompassing a human endogenous retrovirus exhibits marked
upregulation in prostate tumors but not metastases.
[0069] FIG. 4 shows that prostate cancer ncRNAs populate the
Chr8q24 gene desert. a. A schematic of the chr8q24 region. b.
Comprehensive analysis of the chr8q24 region by RNA-Seq and
ChIP-Seq reveals numerous transcripts supported by histone
modifications, such as Acetyl-H3 and H3K4me3, demarcating active
chromatin. c. RT-PCR and Sanger sequencing validation of the PCAT-1
exon-exon junction. d. The genomic location of PCAT-1 determined by
5' and 3' RACE. Sequence analysis of PCAT-1 shows that it is a
viral long terminal repeat (LTR) promoter splicing to a marniner
family transposase that has been bisected by an Alu repeat. e. qPCR
on a panel of prostate and non-prostate samples shows
prostate-specific expression and upregulation in prostate cancers
and metastases compared to benign prostate samples. f. Four matched
tumor/normal pairs included in the analysis in e. demonstrate
somatic upregulation of PCAT-1 in matched cancer samples.
[0070] FIG. 5 shows that ncRNAs serve as urine biomarkers for
prostate cancer. a-c. Three ncRNAs displaying biomarker status in
prostate cancer tissues were evaluated on a cohort of urine samples
from 77 patients with prostate cancer and 31 controls with negative
prostate biopsy results and absence of the TMPRSS2-ERG fusion
transcript. PCA3 (a); PCAT-1 (b); and PCAT-14 (c). d. Scatter plots
demonstrating distinct patient subsets scoring positively for PCA3,
PCAT-1, or PCAT-14 expression. e. A heatmap displaying patients
positive and negative for several different prostate cancer
biomarkers in urine sediment samples. f. A table displaying the
statistical significance of the ncRNA signature. g. A model for
non-coding RNA (ncRNA) activation in prostate cancer.
[0071] FIG. 6 shows Ab initio assembly of the prostate cancer
transcriptome. (a) Reads were mapped with TopHat and assembled into
library-specific transcriptomes by Cufflinks. (b) Transcripts
corresponding to processed pseudogenes were isolated, and the
remaining transcripts were categorized based on overlap with an
aggregated set of known gene annotations.
[0072] FIG. 7 shows classification tree results for Chromosome 1.
The recursive regression and partitioning trees (rpart) machine
learning algorithm was used to predict expressed transcripts versus
background signal.
[0073] FIG. 8 shows transcript assembly of known genes. ab initio
transcript assembly on prostate transcriptome sequencing data was
used to reconstruct the known prostate transcriptome. a. SPINK1, a
biomarker for prostate cancer. b. PRUNE2 with the PCA3 non-coding
RNA within its intronic regions. c. NFKB1. d. COL9A2.
[0074] FIG. 9 shows analysis of EST support for exemplary
transcripts. ESTs from the UCSC database table "Human ESTs" were
used to evaluate the amount of overlap between ESTs and novel
transcripts. a. A line graph showing the fraction of genes whose
transcripts are supported by a particular fraction of ESTs. b. A
table displaying the number of ESTs supporting each class of
transcripts
[0075] FIG. 10 shows analysis of coding potential of unannotated
transcripts. DNA sequences for each transcript were extracted and
searched for open reading frames (ORFs) using the txCdsPredict
program from the UCSC source tool set.
[0076] FIG. 11 shows repetitive content of novel transcripts. The
percentage of repetitive sequences was assessed in all transcripts
by calculating the percentage of repeatmasked nucleotides in each
sequence.
[0077] FIG. 12 shows distinct ChIP-Seq signatures for
repeat-associated and nonrepeat novel ncRNAs. Unannotated
transcripts were divided into two groups, repeat-associated and
non-repeat, and intersected with ChIP-Seq data for Acetyl-H3 and
H3K4me3, two histone modifications strongly associated with
transcriptional start sites (TSS), in two prostate cancer cell
lines. a. Acetyl-H3 in LNCaP cells. b. H3K4me3 in LNCaP cells. c.
Acetyl-H3 in VCaP cells. d. H3K4me3 in VCaP cells.
[0078] FIG. 13 shows overlap of unannotated transcripts with
ChIP-Seq data in VCaP cells. Previously published ChIP-Seq data for
VCaP prostate cancer cells were intersected with unannotated
prostate cancer transcripts and annotated control genes. a. H3K4me1
b. H3K36me3.
[0079] FIG. 14 shows overlap of unannotated transcripts with
ChIP-Seq data in LNCaP cells. ChIP-Seq data for LNCaP prostate
cancer cells were intersected with unannotated transcripts and
annotated control genes. ncRNAs were divided into intergenic and
intronic. a. H3K4me1 b. H3K4me2 c. H3K4me3 d. Acetyl-H3 e. H3K36me3
f. RNA polymerase II.
[0080] FIG. 15 shows validation of a novel transcript on chromosome
15. a. Coverage maps showing the average expression levels (RPKM)
across the benign, localized tumor, and metastatic samples shows
upregulation of a novel transcript downstream of TLE3. b. Several
predicted isoforms of this transcript were nominated which retained
common exons 1 and 2. c. The exon-exon boundary between exons 1 and
2, as well as an internal portion of exon 3, was validated by
RT-PCR in prostate cell line models. d. Sanger sequencing of the
RT-PCR product confirmed the junction of exon 1 and exon 2.
[0081] FIG. 16 shows clustering of prostate cancer with outliers.
Transcripts with outlier profile scores in the top 10% were
clustered using hierarchical trees.
[0082] FIG. 17 shows validation of novel transcripts in prostate
cell lines. 11/14 unannotated transcripts selected for validation
by RT-PCR and qPCR were confirmed in cell line models. a. RT-PCR
gels showing expected bands for the 11 transcripts that validated.
b. Representative qPCR results using primers selected from a. The
primers used in b are indicated by a red asterisk in a.
[0083] FIG. 18 shows that PCAT-14 is upregulated by androgen
signaling. VCaP and LNCaP cells were treated 5 nM R1881 or vehicle
(ethanol) control.
[0084] FIG. 19 shows that PCAT-14 is upregulated in matched tumor
tissues. Four matched tumor-normal patient tissue samples were
assayed for PCAT-14 expression by qPCR.
[0085] FIG. 20 shows analysis of PCAT-14 transcript structure. a.
Representative 5'RACE results using a 3' primer confirms the
presence of the sense transcript PCAT-14. Predicted novel
transcripts are displayed above the RACE results. b. DNA sequence
analysis of PCAT-14 indicates expected splice donor sites, splice
acceptor sites, and a polyadenylation site.
[0086] FIG. 21 shows analysis of PCAT-1 transcript structure. 5'
and 3' RACE experiments showed a ncRNA transcript containing two
exons.
[0087] FIG. 22 shows that knockdown of PCAT-1 does not affect
invasion or proliferation of VCaP cells. VCaP cells were
transfected with custom-made siRNAs targeting PCAT-1 or
non-targeting controls. a. Knockdown efficiency for four siRNA
oligos individually and pooled. b.-d. siRNAs 2-4 were tested for
functional effect due to their higher efficiency of knockdown. b. A
cell proliferation assay performed with a Coulter counter shows no
significant difference in cell proliferation following knockdown of
PCAT-1. c. A WST-1 assay indicates no change in VCaP cell viability
following PCAT-1 knockdown. d. A transmembrane invasion assay shows
no change in VCaP cell invasiveness following PCAT-1 knockdown.
[0088] FIG. 23 shows transcription of two Alu elements in a CACNA1D
intron. a. Coverage maps representing average expression in RPKM in
benign samples, localized tumors, and prostate metastases. b. RPKM
expression values for the CACNA1D Alu transcript across the
prostate transcriptome sequencing cohort. c. RT-PCR validation of
the Alu transcript in cell line models. d. Sanger sequencing
confirmation of RT-PCR fragments verifies the presence of AluSp
transcript sequence. e. Raw sequencing data of a portion of the
AluSp sequence.
[0089] FIG. 24 shows transcription of numerous repeat elements at
the SChLAP1 locus. a. Coverage maps representing repeat elements
transcribed at the chr2q31.3 locus. b. RPKM expression expression
values for the LINE-1 repeat region on chr2q31.3 across the
prostate transcriptome sequencing cohort. c. RTPCR validation of
the LINE-1 repetitive element in cell line models. A 402 bp
fragment was amplified. d. Sanger sequencing of the PCR fragment
confirms identity of the LINE-1 amplicon.
[0090] FIG. 25 shows a heatmap of repeats clusters prostate cancer
samples. Unannotated transcripts that contained repeat elements
were used to cluster prostate cancer samples in an unsupervised
manner.
[0091] FIG. 26 shows that the SChLAP1 locus spans >500 kb.
Visualization of transcriptome sequencing data in the UCSC genome
browser indicates that a large, almost 1 Mb section of chromosome 2
is highly activated in cancer, contributing to many individual
transcripts regulated in a coordinated fashion.
[0092] FIG. 27 shows that the SChLAP1 locus is associated with ETS
positive tumors. a. Expression of the SChLAP1 locus was assayed by
qPCR as display in FIG. 3b on a cohort of 14 benign prostate
tissues, 47 localized prostate tumors and 10 metastatic prostate
cancers. b. Quantification of the SChLAP1 association with ETS
status using the threshold indicated by the blue dotted line in
a.
[0093] FIG. 28 shows the sequence of PCAT-1 and PCAT-14.
[0094] FIG. 29 shows that PCAT-1 expression sensitizes prostate
cancer cells to treatment with PARP-1 inhibitors. (a-d) treatment
with the PARP 1 inhibitor olaparib, (e-h) treatment with the PARP1
inhibitor ABT-888. Stable PCAT-1 knockdown in LNCAP prostate cells
reduces sensitivity to olaparib (a) and ABT-888 (e). Stable
overexpression in Du145 prostate cancer and RWPE benign prostate
cells increases sensitivity to olaparib (b,c) and ABT-888 (f,g).
Overexpression of PCAT-1 in MCF7 breast cancer cells does not
recapitulate this effect (d,h).
[0095] FIG. 30 shows that PCAT-1 expression sensitizes prostate
cancer cells to radiation treatment. (a) Stable PCAT-1 knockdown in
LNCAP prostate cells reduces sensitivity to radiation. (b,c) Stable
overexpression in Du145 prostate cancer and RWPE benign prostate
cells increases sensitivity to radiation. (d). Overexpression of
PCAT-1 in MCF7 breast cancer cells does not recapitulate this
effect.
[0096] FIG. 31 shows that unannotated intergenic transcripts
differentiate prostate cancer and benign samples. (a) The genomic
location and exon structure of SChLAP-1. SChLAP-1 is located on
chromosome 2 in a previously unannotated region. (b) The isoform
structure of SChLAP-1. (c) Cell fractionation into nuclear and
cytoplasmic fractions demonstrates that SChLAP-1 is predominantly
nuclear in its localization. (d) Expression of SChLAP-1 in a cohort
of prostate cancer and benign tissues indicates that SChLAP-1 is a
prostate cancer outlier associated with cancers.
[0097] FIG. 32 shows that SChLAP-1 is required for prostate cancer
cell invasion and proliferation. (a) Prostate and non-prostate
cancer cell lines were treated with SChLAP-1 siRNAs. (b and c) As
in (a), prostate and non-prostate cell lines were assayed for cell
proliferation following SChLAP-1 knockdown. (d) The three most
abundant isoforms of SChLAP-1 were cloned and overexpressed in RWPE
benign immortalized prostate cells at levels similar to LNCaP
cancer cells. (e) RWPE cells overexpressing SChLAP-1 isoforms show
an increased ability to invade through Matrigel in Boyden chamber
assays.
[0098] FIG. 33 shows that deletion analysis of SChLAP-1 identifies
a region essential for its function. (a) RWPE cells overexpressing
SChLAP-1 deletion constructs or full-length isoform #1 were
generated as shown in the schematic of the constructs. (b) RWPE
cells overexpressing SChLAP-1 deletion constructs demonstrated an
impaired ability to invade through Matrigel, while the other
deletion constructs showed no reduction in their ability to induce
RWPE cell invasion compared to the wild type SChLAP-1.
[0099] FIG. 34 shows detection of prostate cancer RNAs in patient
urine samples. (a-e). (a) PCA3 (b) PCAT-14 (c) PCAT-1 (d) SChLAP-1
(e) PDLIM5
[0100] FIG. 35 shows multiplexing urine SChLAP-1 measurements with
serum PSA improves prostate cancer risk stratification.
[0101] FIG. 36 shows analysis of the lung cancer transcriptome. (a)
38 lung cell lines were analyzed by RNA-Seq and then lncRNA
transcripts were reconstructed. (b) Expression levels of
transcripts observed in lung cell lines. (c) An outlier analyses of
13 unannotated transcripts shows the presence of novel lncRNAs in
subtypes of lung cancer cell lines.
[0102] FIG. 37 shows discovery of M41 and ENST-75 in lung cancer.
(a) The genomic location of M41, which resides in an intron of
DSCAM. M41 is poorly conserved across species. (b) qPCR of M41
demonstrates outlier expression in 15-20% of lung adenocarcinomas
as well as high expression in breast cells. (c) The genomic
location of ENST-75, which demonstrates high conservation across
species. (d) qPCR of ENST-75 shows up-regulation in lung cancer but
not breast or prostate cancers. High expression is observed in
normal testis.
[0103] FIG. 38 shows lncRNAs are drivers and biomarkers in lung
cancer. (a) Knockdown of ENST-75 in H1299 cells with independent
siRNAs achieving >70% knockdown. (b) Knockdown of ENST-75 in
H1299 cells impairs cell proliferation. Error bars represent s.e.m.
(c) ENST-75 expression in lung adenocarcinomas stratifies patient
overall survival. (d) Serum detection levels of ENST-75 in normal
and lung cancer patients. (e) Average ENST-75 expression in lung
cancer patient sera compared to normal patient sera. Error bars
represent s.e.m.
[0104] FIG. 39 shows nomination of cancer-associated lncRNAs in
breast and pancreatic cancer. (a-c) (a) TU0011194 (b) TU0019356 (c)
TU0024146 (d-f) Three novel pancreatic cancer lncRNAs nominated
from RNA-Seq data. All show outlier expression patterns in
pancreatic cancer samples but not benign samples. (d) TU0009141 (e)
TU0062051 (f) TU0021861.
[0105] FIG. 40 shows discovery of SChLAP-1 as a prostate cancer
lncRNA. (a) Cancer outlier profile analysis (COPA) for intergenic
lncRNAs in prostate cancer nominates two transcripts, PCAT-109 and
PCAT-114, as prominent outliers. (b) A comparison of lncRNA
outliers nominated by COPA, including their location, frequency in
clinical samples, their expression in tissues and cell lines, and
whether they occur in metastatic prostate samples. (c) A
representation of the SChLAP-1 gene and its annotations in current
databases. SChLAP-1 may consist of up to seven exons on Chr2q31.3.
(d) A schematic summarizing the observed SChLAP-1 isoforms. (e)
qPCR for SChLAP-1 on a panel of benign prostate (n=33), localized
prostate cancer (n=82), and metastatic prostate cancer (n=33)
samples. (f) SChLAP-1 expression is predominantly nuclear.
[0106] FIG. 41 shows that SChLAP-1 coordinates prostate cancer cell
invasion. (a) siRNA knockdown of SChLAP-1 in vitro. (b)
Overexpression of SChLAP-1 in RWPE cells. (c) Deletion analysis of
SChLAP-1. (d) RNA structural analysis of SChLAP-1. (e) Tumor
seeding with SChLAP-1 knockdown in vivo. (f) The number of gross
metastatic sites observed by luciferase signal in 22Rv1 shSChLAP-1
cells or shNT controls. (g) Example luciferase bioluminescence
images from 22Rv1 shNT, shSChLAP-1 #1, and shSChLAP-1 #2 mice five
weeks following intracardiac injection.
[0107] FIG. 42 shows that SChLAP-1 antagonizes SWI/SNF complex
function. (a) Gene set enrichment analysis (GSEA) of LNCaP and
22Rv1 cells treated with SChLAP-1 siRNAs. (b) Heatmap results for
SChLAP-1 or SWI/SNF knockdown in LNCaP and 22Rv1 cells. (c) GSEA
analysis of SChLAP-1 and SWI/SNF knockdowns. (d) RNA
immunoprecipitation (RIP) of SNF5 and AR demonstrates SChLAP-1
binding to SNF5 in 22Rv1 and LNCaP cells. (e) RIP analysis of SNF5
in RWPE cells overexpressing LacZ, SChLAP-1 isoform #1, SChLAP-1
isoform #2, or SChLAP-1 deletion construct 5.
[0108] FIG. 43 shows that SChLAP-1 expression characterizes
aggressive prostate cancer. (a) Network representation of Oncomine
concepts analysis of genes positively and negatively correlated
with SChLAP-1 expression levels in localized prostate cancers
profiled by RNA-Seq. (b) Heatmap representation of comparisons
between co-expression gene signatures and molecular concepts. (c-e)
Kaplan-Meier analyses of prostate cancer outcomes in the Mayo
Clinic cohort. (c), clinical progression to systemic disease (d),
and prostate cancer-specific mortality (e). (f) A model of SChLAP-1
activity in prostate cancer.
[0109] FIG. 44 shows that chromosome 2 region contains prostate
cancer-associated transcripts.
[0110] FIG. 45 shows the structure and sequence of SChLAP1.
[0111] FIG. 46 shows expression of SChLAP-1 across cancers.
DEFINITIONS
[0112] To facilitate an understanding of the present invention, a
number of terms and phrases are defined below:
[0113] As used herein, the terms "detect", "detecting" or
"detection" may describe either the general act of discovering or
discerning or the specific observation of a composition. Detecting
a composition may comprise determining the presence or absence of a
composition. Detecting may comprise quantifying a composition. For
example, detecting comprises determining the expression level of a
composition. The composition may comprise a nucleic acid molecule.
For example, the composition may comprise at least a portion of the
ncRNAs disclosed herein. Alternatively, or additionally, the
composition may be a detectably labeled composition.
[0114] As used herein, the term "subject" refers to any organisms
that are screened using the diagnostic methods described herein.
Such organisms preferably include, but are not limited to, mammals
(e.g., murines, simians, equines, bovines, porcines, canines,
felines, and the like), and most preferably includes humans.
Alternatively, the organism is an avian, amphibian, reptile or
fish.
[0115] The term "diagnosed," as used herein, refers to the
recognition of a disease by its signs and symptoms, or genetic
analysis, pathological analysis, histological analysis, and the
like.
[0116] A "subject suspected of having cancer" encompasses an
individual who has received an initial diagnosis (e.g., a CT scan
showing a mass or increased PSA level) but for whom the stage of
cancer or presence or absence of ncRNAs indicative of cancer is not
known. The term further includes people who once had cancer (e.g.,
an individual in remission). In some embodiments, "subjects" are
control subjects that are suspected of having cancer or diagnosed
with cancer.
[0117] As used herein, the term "characterizing cancer in a
subject" refers to the identification of one or more properties of
a cancer sample in a subject, including but not limited to, the
presence of benign, pre-cancerous or cancerous tissue, the stage of
the cancer, and the subject's prognosis. Cancers may be
characterized by the identification of the expression of one or
more cancer marker genes, including but not limited to, the ncRNAs
disclosed herein.
[0118] As used herein, the term "characterizing prostate tissue in
a subject" refers to the identification of one or more properties
of a prostate tissue sample (e.g., including but not limited to,
the presence of cancerous tissue, the presence or absence of
ncRNAs, the presence of pre-cancerous tissue that is likely to
become cancerous, and the presence of cancerous tissue that is
likely to metastasize). In some embodiments, tissues are
characterized by the identification of the expression of one or
more cancer marker genes, including but not limited to, the cancer
markers disclosed herein.
[0119] As used herein, the term "stage of cancer" refers to a
qualitative or quantitative assessment of the level of advancement
of a cancer. Criteria used to determine the stage of a cancer
include, but are not limited to, the size of the tumor and the
extent of metastases (e.g., localized or distant).
[0120] As used herein, the term "nucleic acid molecule" refers to
any nucleic acid containing molecule, including but not limited to,
DNA or RNA. The nucleic acid molecule may comprise one or more
nucleotides. The term encompasses sequences that include any of the
known base analogs of DNA and RNA including, but not limited to,
4-acetylcytosine, 8-hydroxy-N6-methyladenosine, aziridinylcytosine,
pseudoisocytosine, 5-(carboxyhydroxylmethyl) uracil,
5-fluorouracil, 5-bromouracil,
5-carboxymethylaminomethyl-2-thiouracil,
5-carboxymethyl-aminomethyluracil, dihydrouracil, inosine,
N6-isopentenyladenine, 1-methyladenine, 1-methylpseudouracil,
1-methylguanine, 1-methylinosine, 2,2-dimethylguanine,
2-methyladenine, 2-methylguanine, 3-methylcytosine,
5-methylcytosine, N6-methyladenine, 7-methylguanine,
5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil,
beta-D-mannosylqueosine, 5'-methoxycarbonylmethyluracil,
5-methoxyuracil, 2-methylthio-N6-isopentenyladenine,
uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid,
oxybutoxosine, pseudouracil, queosine, 2-thiocytosine,
5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,
N-uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid,
pseudouracil, queosine, 2-thiocytosine, and 2,6-diaminopurine.
[0121] The term "gene" refers to a nucleic acid (e.g., DNA)
sequence that comprises coding sequences necessary for the
production of a polypeptide, precursor, or RNA (e.g., rRNA, tRNA).
The polypeptide can be encoded by a full length coding sequence or
by any portion of the coding sequence so long as the desired
activity or functional properties (e.g., enzymatic activity, ligand
binding, signal transduction, immunogenicity, etc.) of the
full-length or fragments are retained. The term also encompasses
the coding region of a structural gene and the sequences located
adjacent to the coding region on both the 5' and 3' ends for a
distance of about 1 kb or more on either end such that the gene
corresponds to the length of the full-length mRNA. Sequences
located 5' of the coding region and present on the mRNA are
referred to as 5' non-translated sequences. Sequences located 3' or
downstream of the coding region and present on the mRNA are
referred to as 3' non-translated sequences. The term "gene"
encompasses both cDNA and genomic forms of a gene. A genomic form
or clone of a gene contains the coding region interrupted with
non-coding sequences termed "introns" or "intervening regions" or
"intervening sequences." Introns are segments of a gene that are
transcribed into nuclear RNA (hnRNA); introns may contain
regulatory elements such as enhancers. Introns are removed or
"spliced out" from the nuclear or primary transcript; introns
therefore are absent in the messenger RNA (mRNA) transcript. The
mRNA functions during translation to specify the sequence or order
of amino acids in a nascent polypeptide.
[0122] As used herein, the term "oligonucleotide," refers to a
short length of single-stranded polynucleotide chain.
Oligonucleotides are typically less than 200 residues long (e.g.,
between 15 and 100), however, as used herein, the term is also
intended to encompass longer polynucleotide chains.
Oligonucleotides are often referred to by their length. For example
a 24 residue oligonucleotide is referred to as a "24-mer".
Oligonucleotides can form secondary and tertiary structures by
self-hybridizing or by hybridizing to other polynucleotides. Such
structures can include, but are not limited to, duplexes, hairpins,
cruciforms, bends, and triplexes.
[0123] As used herein, the terms "complementary" or
"complementarity" are used in reference to polynucleotides (i.e., a
sequence of nucleotides) related by the base-pairing rules. For
example, the sequence "5'-A-G-T-3'," is complementary to the
sequence "3'-T-C-A-5'." Complementarity may be "partial," in which
only some of the nucleic acids' bases are matched according to the
base pairing rules. Or, there may be "complete" or "total"
complementarity between the nucleic acids. The degree of
complementarity between nucleic acid strands has significant
effects on the efficiency and strength of hybridization between
nucleic acid strands. This is of particular importance in
amplification reactions, as well as detection methods that depend
upon binding between nucleic acids.
[0124] The term "homology" refers to a degree of complementarity.
There may be partial homology or complete homology (i.e.,
identity). A partially complementary sequence is a nucleic acid
molecule that at least partially inhibits a completely
complementary nucleic acid molecule from hybridizing to a target
nucleic acid is "substantially homologous." The inhibition of
hybridization of the completely complementary sequence to the
target sequence may be examined using a hybridization assay
(Southern or Northern blot, solution hybridization and the like)
under conditions of low stringency. A substantially homologous
sequence or probe will compete for and inhibit the binding (i.e.,
the hybridization) of a completely homologous nucleic acid molecule
to a target under conditions of low stringency. This is not to say
that conditions of low stringency are such that non-specific
binding is permitted; low stringency conditions require that the
binding of two sequences to one another be a specific (i.e.,
selective) interaction. The absence of non-specific binding may be
tested by the use of a second target that is substantially
non-complementary (e.g., less than about 30% identity); in the
absence of non-specific binding the probe will not hybridize to the
second non-complementary target.
[0125] As used herein, the term "hybridization" is used in
reference to the pairing of complementary nucleic acids.
Hybridization and the strength of hybridization (i.e., the strength
of the association between the nucleic acids) is impacted by such
factors as the degree of complementary between the nucleic acids,
stringency of the conditions involved, the T.sub.m of the formed
hybrid, and the G:C ratio within the nucleic acids. A single
molecule that contains pairing of complementary nucleic acids
within its structure is said to be "self-hybridized."
[0126] As used herein the term "stringency" is used in reference to
the conditions of temperature, ionic strength, and the presence of
other compounds such as organic solvents, under which nucleic acid
hybridizations are conducted. Under "low stringency conditions" a
nucleic acid sequence of interest will hybridize to its exact
complement, sequences with single base mismatches, closely related
sequences (e.g., sequences with 90% or greater homology), and
sequences having only partial homology (e.g., sequences with 50-90%
homology). Under `medium stringency conditions," a nucleic acid
sequence of interest will hybridize only to its exact complement,
sequences with single base mismatches, and closely relation
sequences (e.g., 90% or greater homology). Under "high stringency
conditions," a nucleic acid sequence of interest will hybridize
only to its exact complement, and (depending on conditions such a
temperature) sequences with single base mismatches. In other words,
under conditions of high stringency the temperature can be raised
so as to exclude hybridization to sequences with single base
mismatches.
[0127] The term "isolated" when used in relation to a nucleic acid,
as in "an isolated oligonucleotide" or "isolated polynucleotide"
refers to a nucleic acid sequence that is identified and separated
from at least one component or contaminant with which it is
ordinarily associated in its natural source. Isolated nucleic acid
is such present in a form or setting that is different from that in
which it is found in nature. In contrast, non-isolated nucleic
acids as nucleic acids such as DNA and RNA found in the state they
exist in nature. For example, a given DNA sequence (e.g., a gene)
is found on the host cell chromosome in proximity to neighboring
genes; RNA sequences, such as a specific mRNA sequence encoding a
specific protein, are found in the cell as a mixture with numerous
other mRNAs that encode a multitude of proteins. However, isolated
nucleic acid encoding a given protein includes, by way of example,
such nucleic acid in cells ordinarily expressing the given protein
where the nucleic acid is in a chromosomal location different from
that of natural cells, or is otherwise flanked by a different
nucleic acid sequence than that found in nature. The isolated
nucleic acid, oligonucleotide, or polynucleotide may be present in
single-stranded or double-stranded form. When an isolated nucleic
acid, oligonucleotide or polynucleotide is to be utilized to
express a protein, the oligonucleotide or polynucleotide will
contain at a minimum the sense or coding strand (i.e., the
oligonucleotide or polynucleotide may be single-stranded), but may
contain both the sense and anti-sense strands (i.e., the
oligonucleotide or polynucleotide may be double-stranded).
[0128] As used herein, the term "purified" or "to purify" refers to
the removal of components (e.g., contaminants) from a sample. For
example, antibodies are purified by removal of contaminating
non-immunoglobulin proteins; they are also purified by the removal
of immunoglobulin that does not bind to the target molecule. The
removal of non-immunoglobulin proteins and/or the removal of
immunoglobulins that do not bind to the target molecule results in
an increase in the percent of target-reactive immunoglobulins in
the sample. In another example, recombinant polypeptides are
expressed in bacterial host cells and the polypeptides are purified
by the removal of host cell proteins; the percent of recombinant
polypeptides is thereby increased in the sample.
[0129] As used herein, the term "sample" is used in its broadest
sense. In one sense, it is meant to include a specimen or culture
obtained from any source, as well as biological and environmental
samples. Biological samples may be obtained from animals (including
humans) and encompass fluids, solids, tissues, and gases.
Biological samples include blood products, such as plasma, serum
and the like. Such examples are not however to be construed as
limiting the sample types applicable to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0130] The present invention relates to compositions and methods
for cancer diagnosis, research and therapy, including but not
limited to, cancer markers. In particular, the present invention
relates to ncRNAs as diagnostic markers and clinical targets for
cancer. ncRNAs may be used as diagnostic markers and clinical
targets for prostate, lung, breast and pancreatic cancer.
[0131] Experiments conducted during the development of embodiments
of the present invention utilized RNA-Seq analyses of tissue
samples and ab initio transcriptome assembly to predict the
complete polyA+ transcriptome of prostate cancer. 6,144 novel
ncRNAs found in prostate cancer were identified, including 121
ncRNAs that associated with disease progression (FIGS. 1, 2, 16 and
25). These data demonstrate the global utility of RNA-Seq in
defining functionally-important elements of the genome.
[0132] The present invention is not limited to a particular
mechanism. Indeed, an understanding of the mechanism is not
necessary to practice the present invention. Nonetheless, although
the biological role of these RNAs, especially the
differentially-expressed ones, is not yet known, these results
indicate a model in which specific intergenic loci are activated in
prostate cancer, enabling the transcription of numerous
disease-specific and tissue-specific ncRNAs (FIG. 5g). Clinically,
these ncRNA signatures are suitable for urine-based assays to
detect and diagnose prostate cancer in a non-invasive manner (See
e.g., Example 1). It is further contemplated that specific ncRNA
signatures occur universally in all disease states and applying
these methodologies to other diseases reveals clinically important
biomarkers, particularly for diseases that currently lack good
protein biomarkers.
[0133] While traditional approaches have focused on the annotated
reference genome, data generated during the course of development
of embodiments of the present invention implicate large swaths of
unannotated genomic loci in prostate cancer progression and
prostate-specific expression. One example of this is the SChLAP1
locus, which represents a >500 kb stretch of coordinately
regulated expression, and the chr8q24 locus, which contains a
prostate specific region with the prostate cancer biomarker PCAT-1.
The fact that the SChLAP 1 locus is almost exclusively expressed in
prostate cancers harboring an ETS gene fusion further confirms the
capacity of ncRNAs to identify patient disease subtypes. In
addition, these analyses reveal novel cancer-specific drivers of
tumorigenesis. For example, the long ncRNA HOTAIR is known to
direct cancer-promoting roles for EZH2 in breast cancer (Gupta et
al., Nature 464 (7291), 1071 (2010)), while in the PC3 prostate
cancer cell line a similar role has been proposed for the ANRIL
ncRNA (Yap et al., Mol Cell 38 (5), 662 (2010)).
I. Diagnostic and Screening Methods
[0134] As described herein, embodiments of the present invention
provide diagnostic and screening methods that utilize the detection
of one or more ncRNAs. Exemplary ncRNAs include, but are not
limited to, PCAT-1, PCAT-14, PCAT-43 and PCAT-109; SChLAP-1; and
SEQ ID NOs: 1-9. Exemplary, non-limiting methods are described
herein.
[0135] Any patient sample suspected of containing the ncRNAs may be
tested according to methods of embodiments of the present
invention. By way of non-limiting examples, the sample may be
tissue (e.g., a biopsy sample, a prostate biopsy sample or a tissue
sample obtained by prostatectomy), blood, urine, semen, prostatic
secretions or a fraction thereof (e.g., plasma, serum, urine
supernatant, urine cell pellet, cells or prostate cells). A urine
sample may be collected immediately following an attentive digital
rectal examination (DRE), which causes prostate cells from the
prostate gland to shed into the urinary tract.
[0136] In some embodiments, the patient sample is subjected to
preliminary processing designed to isolate or enrich the sample for
the ncRNAs or cells that contain the ncRNAs. A variety of
techniques known to those of ordinary skill in the art may be used
for this purpose, including but not limited to: centrifugation;
immunocapture; cell lysis; nucleic acid amplification; and, nucleic
acid target capture (See, e.g., EP Pat. No. 1 409 727, herein
incorporated by reference in its entirety).
[0137] The ncRNAs may be detected along with other markers in a
multiplex or panel format. Markers may be selected for their
predictive value alone or in combination with the gene fusions.
Exemplary prostate cancer markers include, but are not limited to:
AMACR/P504S (U.S. Pat. No. 6,262,245); PCA3 (U.S. Pat. No.
7,008,765); PCGEM1 (U.S. Pat. No. 6,828,429); prostein/P501S,
P503S, P504S, P509S, P510S, prostase/P703P, P710P (U.S. Publication
No. 20030185830); RAS/KRAS (Bos, Cancer Res. 49:4682-89 (1989);
Kranenburg, Biochimica et Biophysica Acta 1756:81-82 (2005)); and,
those disclosed in U.S. Pat. Nos. 5,854,206 and 6,034,218,
7,229,774, each of which is herein incorporated by reference in its
entirety. Markers for other cancers, diseases, infections, and
metabolic conditions are also contemplated for inclusion in a
multiplex or panel format.
[0138] In some embodiments, multiplex or array formats are utilized
to detect multiple markers in combination. For example, in some
embodiments, the level of expression of one or more, 2 or more, 3
or more, 4 or more, 5 or more, 10 or more, 15 or more, 20 or more,
25 or more, 30 or more, 35 or more, 40 or more 45 or more, 50 or
more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more
or all 121) non-coding RNAs (ncRNAs) is utilized in the research,
screening, diagnostic and prognositic compositions and methods
described herein. The one or more ncRNAs may be selected from the
group comprising SChLAP-1, PCAT1, PCAT2, PCAT3, PCAT4, PCAT5,
PCAT6, PCAT7, PCAT8, PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14,
PCAT15, PCAT16, PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22,
PCAT23, PCAT24, PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30,
PCAT31, PCAT32, PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38,
PCAT39, PCAT40, PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46,
PCAT47, PCAT48, PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54,
PCAT55, PCAT56, PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62,
PCAT63, PCAT64, PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70,
PCAT71, PCAT72, PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78,
PCAT79, PCAT80, PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86,
PCAT87, PCAT88, PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94,
PCAT95, PCAT96, PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102,
PCAT103, PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109,
PCAT110, PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116,
PCAT117, PCAT118, PCAT119, PCAT120, and PCAT121.
i. DNA and RNA Detection
[0139] The ncRNAs of the present invention are detected using a
variety of nucleic acid techniques known to those of ordinary skill
in the art, including but not limited to: nucleic acid sequencing;
nucleic acid hybridization; and, nucleic acid amplification.
[0140] The methods, compositions and kits may comprise one or more
ncRNAs. The methods, compositions and kits may comprise 2 or more,
3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9
or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or
more, 40 or more, 45 or more, 50 or more, 55 or more, 60 or more,
70 or more, 80 or more, 90 or more, 100 or more, 110 or more, 120
or more, 130 or more, 140 or more, 150 or more ncRNAs.
[0141] The one or more ncRNAs may be selected from the group
comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8,
PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16,
PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23, PCAT24,
PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,
PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40,
PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48,
PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,
PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64,
PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72,
PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80,
PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88,
PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95, PCAT96,
PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,
PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110,
PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117,
PCAT118, PCAT119, PCAT120, PCAT121, SChLAP-1, TU0011194, TU0019356,
TU0024146, TU0009141, TU0062051, TU0021861, M41, ENST-75, and SEQ
ID NOs: 1-9. The one or more ncRNAs of the present invention may
comprise one or more prostate cancer-associated ncRNA transcripts
(PCATs). The one or more PCATs may be selected from the group
comprising PCAT1, PCAT2, PCAT3, PCAT4, PCAT5, PCAT6, PCAT7, PCAT8,
PCAT9, PCAT10, PCAT11, PCAT12, PCAT13, PCAT14, PCAT15, PCAT16,
PCAT17, PCAT18, PCAT19, PCAT20, PCAT21, PCAT22, PCAT23, PCAT24,
PCAT25, PCAT26, PCAT27, PCAT28, PCAT29, PCAT30, PCAT31, PCAT32,
PCAT33, PCAT34, PCAT35, PCAT36, PCAT37, PCAT38, PCAT39, PCAT40,
PCAT41, PCAT42, PCAT43, PCAT44, PCAT45, PCAT46, PCAT47, PCAT48,
PCAT49, PCAT50, PCAT51, PCAT52, PCAT53, PCAT54, PCAT55, PCAT56,
PCAT57, PCAT58, PCAT59, PCAT60, PCAT61, PCAT62, PCAT63, PCAT64,
PCAT65, PCAT66, PCAT67, PCAT68, PCAT69, PCAT70, PCAT71, PCAT72,
PCAT73, PCAT74, PCAT75, PCAT76, PCAT77, PCAT78, PCAT79, PCAT80,
PCAT81, PCAT82, PCAT83, PCAT84, PCAT85, PCAT86, PCAT87, PCAT88,
PCAT89, PCAT90, PCAT91, PCAT92, PCAT93, PCAT94, PCAT95, PCAT96,
PCAT97, PCAT98, PCAT99, PCAT100, PCAT101, PCAT102, PCAT103,
PCAT104, PCAT105, PCAT106, PCAT107, PCAT108, PCAT109, PCAT110,
PCAT111, PCAT112, PCAT113, PCAT114, PCAT115, PCAT116, PCAT117,
PCAT118, PCAT119, PCAT120, and PCAT121. The one or more ncRNAs may
comprise PCAT1, PCAT14, PCAT43, PCAT 109, or a combination
thereof.
[0142] Alternatively, or additionally, the ncRNAs of the present
invention may comprise SChLAP-1. The ncRNAs may comprise M41,
ENST-75, or a combination thereof. The ncRNAs may comprise
TU0011194, TU0019356, TU0024146, or a combination thereof. The
ncRNAs may comprise TU0009141, TU0062051, TU0021861 or a
combination thereof. The ncRNAs may comprise any one of SEQ ID NOs:
1-9 or a combination thereof.
[0143] 1. Sequencing
[0144] Illustrative non-limiting examples of nucleic acid
sequencing techniques include, but are not limited to, chain
terminator (Sanger) sequencing and dye terminator sequencing. Those
of ordinary skill in the art will recognize that because RNA is
less stable in the cell and more prone to nuclease attack
experimentally RNA is usually reverse transcribed to DNA before
sequencing.
[0145] Chain terminator sequencing uses sequence-specific
termination of a DNA synthesis reaction using modified nucleotide
substrates. Extension is initiated at a specific site on the
template DNA by using a short radioactive, or other labeled,
oligonucleotide primer complementary to the template at that
region. The oligonucleotide primer is extended using a DNA
polymerase, standard four deoxynucleotide bases, and a low
concentration of one chain terminating nucleotide, most commonly a
di-deoxynucleotide. This reaction is repeated in four separate
tubes with each of the bases taking turns as the
di-deoxynucleotide. Limited incorporation of the chain terminating
nucleotide by the DNA polymerase results in a series of related DNA
fragments that are terminated only at positions where that
particular di-deoxynucleotide is used. For each reaction tube, the
fragments are size-separated by electrophoresis in a slab
polyacrylamide gel or a capillary tube filled with a viscous
polymer. The sequence is determined by reading which lane produces
a visualized mark from the labeled primer as you scan from the top
of the gel to the bottom.
[0146] Dye terminator sequencing alternatively labels the
terminators. Complete sequencing can be performed in a single
reaction by labeling each of the di-deoxynucleotide
chain-terminators with a separate fluorescent dye, which fluoresces
at a different wavelength.
[0147] A variety of nucleic acid sequencing methods are
contemplated for use in the methods of the present disclosure
including, for example, chain terminator (Sanger) sequencing, dye
terminator sequencing, and high-throughput sequencing methods. Many
of these sequencing methods are well known in the art. See, e.g.,
Sanger et al., Proc. Natl. Acad. Sci. USA 74:5463-5467 (1997);
Maxam et al., Proc. Natl. Acad. Sci. USA 74:560-564 (1977);
Drmanac, et al., Nat. Biotechnol. 16:54-58 (1998); Kato, Int. J.
Clin. Exp. Med. 2:193-202 (2009); Ronaghi et al., Anal. Biochem.
242:84-89 (1996); Margulies et al., Nature 437:376-380 (2005);
Ruparel et al., Proc. Natl. Acad. Sci. USA 102:5932-5937 (2005),
and Harris et al., Science 320:106-109 (2008); Levene et al.,
Science 299:682-686 (2003); Korlach et al., Proc. Natl. Acad. Sci.
USA 105:1176-1181 (2008); Branton et al., Nat. Biotechnol.
26(10):1146-53 (2008); Eid et al., Science 323:133-138 (2009); each
of which is herein incorporated by reference in its entirety.
[0148] The methods disclosed herein can comprise transcriptome
sequencing (e.g., RNA-Seq). Sequencing can comprise platforms such
as the Illumina Genome Analyzer platform, ABI Solid Sequencing or
Life Science's 454 Sequencing. Alternatively, sequencing comprises
Helicos' Direct RNA Sequencing (DRS.TM.) technology. The sequencing
reactions may comprise capillary sequencing, next generation
sequencing, Sanger sequencing, sequencing by synthesis, single
molecule nanopore sequencing, sequencing by ligation, sequencing by
hybridization, sequencing by nanopore current restriction, or a
combination thereof. Sequencing by synthesis may comprise
reversible terminator sequencing, processive single molecule
sequencing, sequential nucleotide flow sequencing, or a combination
thereof. Sequential nucleotide flow sequencing may comprise
pyrosequencing, pH-mediated sequencing, semiconductor sequencing or
a combination thereof. Conducting one or more sequencing reactions
comprises whole genome sequencing or exome sequencing.
[0149] 2. Hybridization
[0150] Illustrative non-limiting examples of nucleic acid
hybridization techniques include, but are not limited to, in situ
hybridization (ISH), microarray, and Southern or Northern blot. In
situ hybridization (ISH) is a type of hybridization that uses a
labeled complementary DNA or RNA strand as a probe to localize a
specific DNA or RNA sequence in a portion or section of tissue (in
situ), or, if the tissue is small enough, the entire tissue (whole
mount ISH). DNA ISH can be used to determine the structure of
chromosomes. RNA ISH is used to measure and localize mRNAs and
other transcripts (e.g., ncRNAs) within tissue sections or whole
mounts. Sample cells and tissues are usually treated to fix the
target transcripts in place and to increase access of the probe.
The probe hybridizes to the target sequence at elevated
temperature, and then the excess probe is washed away. The probe
that was labeled with either radio-, fluorescent- or
antigen-labeled bases is localized and quantitated in the tissue
using either autoradiography, fluorescence microscopy or
immunohistochemistry, respectively. ISH can also use two or more
probes, labeled with radioactivity or the other non-radioactive
labels, to simultaneously detect two or more transcripts.
[0151] In some embodiments, ncRNAs are detected using fluorescence
in situ hybridization (FISH). In some embodiments, FISH assays
utilize bacterial artificial chromosomes (BACs). These have been
used extensively in the human genome sequencing project (see Nature
409: 953-958 (2001)) and clones containing specific BACs are
available through distributors that can be located through many
sources, e.g., NCBI. Each BAC clone from the human genome has been
given a reference name that unambiguously identifies it. These
names can be used to find a corresponding GenBank sequence and to
order copies of the clone from a distributor.
[0152] The present invention further provides a method of
performing a FISH assay on the patient sample. The methods
disclosed herein may comprise performing a FISH assay on one or
more cells, tissues, organs, or fluids surrounding such cells,
tissues and organs. In some instances, the methods disclosed herein
further comprise performing a FISH assay on human prostate cells,
human prostate tissue or on the fluid surrounding said human
prostate cells or human prostate tissue. Alternatively, or
additionally, the methods disclosed herein comprise performing a
FISH assay on breast cells, lung cells, pancreatic cells, liver
cells, breast tissue, lung tissue, pancreatic tissue, liver tissue,
or on the fluid surrounding the cells or tissues. Specific
protocols are well known in the art and can be readily adapted for
the present invention. Guidance regarding methodology may be
obtained from many references including: In situ Hybridization:
Medical Applications (eds. G. R. Coulton and J. de Belleroche),
Kluwer Academic Publishers, Boston (1992); In situ Hybridization:
In Neurobiology; Advances in Methodology (eds. J. H. Eberwine, K.
L. Valentino, and J. D. Barchas), Oxford University Press Inc.,
England (1994); In situ Hybridization: A Practical Approach (ed. D.
G. Wilkinson), Oxford University Press Inc., England (1992)); Kuo,
et al., Am. J. Hum. Genet. 49:112-119 (1991); Klinger, et al., Am.
J. Hum. Genet. 51:55-65 (1992); and Ward, et al., Am. J. Hum.
Genet. 52:854-865 (1993)). There are also kits that are
commercially available and that provide protocols for performing
FISH assays (available from e.g., Oncor, Inc., Gaithersburg, Md.).
Patents providing guidance on methodology include U.S. Pat. Nos.
5,225,326; 5,545,524; 6,121,489 and 6,573,043. All of these
references are hereby incorporated by reference in their entirety
and may be used along with similar references in the art and with
the information provided in the Examples section herein to
establish procedural steps convenient for a particular
laboratory.
[0153] The one or more ncRNAs may be detected by conducting one or
more hybridization reactions. The one or more hybridization
reactions may comprise one or more hybridization arrays,
hybridization reactions, hybridization chain reactions, isothermal
hybridization reactions, nucleic acid hybridization reactions, or a
combination thereof. The one or more hybridization arrays may
comprise hybridization array genotyping, hybridization array
proportional sensing, DNA hybridization arrays, macroarrays,
microarrays, high-density oligonucleotide arrays, genomic
hybridization arrays, comparative hybridization arrays, or a
combination thereof.
[0154] 3. Microarrays
[0155] Different kinds of biological assays are called microarrays
including, but not limited to: DNA microarrays (e.g., cDNA
microarrays and oligonucleotide microarrays); protein microarrays;
tissue microarrays; transfection or cell microarrays; chemical
compound microarrays; and, antibody microarrays. A DNA microarray,
commonly known as gene chip, DNA chip, or biochip, is a collection
of microscopic DNA spots attached to a solid surface (e.g., glass,
plastic or silicon chip) forming an array for the purpose of
expression profiling or monitoring expression levels for thousands
of genes simultaneously. The affixed DNA segments are known as
probes, thousands of which can be used in a single DNA microarray.
Microarrays can be used to identify disease genes or transcripts
(e.g., ncRNAs) by comparing gene expression in disease and normal
cells. Microarrays can be fabricated using a variety of
technologies, including but not limiting: printing with
fine-pointed pins onto glass slides; photolithography using
pre-made masks; photolithography using dynamic micromirror devices;
ink-jet printing; or, electrochemistry on microelectrode
arrays.
[0156] 3. Amplification
[0157] The methods disclosed herein may comprise conducting one or
more amplification reactions. Nucleic acids (e.g., ncRNAs) may be
amplified prior to or simultaneous with detection. Conducting one
or more amplification reactions may comprise one or more PCR-based
amplifications, non-PCR based amplifications, or a combination
thereof. Illustrative non-limiting examples of nucleic acid
amplification techniques include, but are not limited to,
polymerase chain reaction (PCR), reverse transcription polymerase
chain reaction (RT-PCR), nested PCR, linear amplification, multiple
displacement amplification (MDA), real-time SDA, rolling circle
amplification, circle-to-circle amplification
transcription-mediated amplification (TMA), ligase chain reaction
(LCR), strand displacement amplification (SDA), and nucleic acid
sequence based amplification (NASBA). Those of ordinary skill in
the art will recognize that certain amplification techniques (e.g.,
PCR) require that RNA be reversed transcribed to DNA prior to
amplification (e.g., RT-PCR), whereas other amplification
techniques directly amplify RNA (e.g., TMA and NASBA).
[0158] The polymerase chain reaction (U.S. Pat. Nos. 4,683,195,
4,683,202, 4,800,159 and 4,965,188, each of which is herein
incorporated by reference in its entirety), commonly referred to as
PCR, uses multiple cycles of denaturation, annealing of primer
pairs to opposite strands, and primer extension to exponentially
increase copy numbers of a target nucleic acid sequence. In a
variation called RT-PCR, reverse transcriptase (RT) is used to make
a complementary DNA (cDNA) from mRNA, and the cDNA is then
amplified by PCR to produce multiple copies of DNA. For other
various permutations of PCR see, e.g., U.S. Pat. Nos. 4,683,195,
4,683,202 and 4,800,159; Mullis et al., Meth. Enzymol. 155: 335
(1987); and, Murakawa et al., DNA 7: 287 (1988), each of which is
herein incorporated by reference in its entirety.
[0159] Transcription mediated amplification (U.S. Pat. Nos.
5,480,784 and 5,399,491, each of which is herein incorporated by
reference in its entirety), commonly referred to as TMA,
synthesizes multiple copies of a target nucleic acid sequence
autocatalytically under conditions of substantially constant
temperature, ionic strength, and pH in which multiple RNA copies of
the target sequence autocatalytically generate additional copies.
See, e.g., U.S. Pat. Nos. 5,399,491 and 5,824,518, each of which is
herein incorporated by reference in its entirety. In a variation
described in U.S. Publ. No. 20060046265 (herein incorporated by
reference in its entirety), TMA optionally incorporates the use of
blocking moieties, terminating moieties, and other modifying
moieties to improve TMA process sensitivity and accuracy.
[0160] The ligase chain reaction (Weiss, R., Science 254: 1292
(1991), herein incorporated by reference in its entirety), commonly
referred to as LCR, uses two sets of complementary DNA
oligonucleotides that hybridize to adjacent regions of the target
nucleic acid. The DNA oligonucleotides are covalently linked by a
DNA ligase in repeated cycles of thermal denaturation,
hybridization and ligation to produce a detectable double-stranded
ligated oligonucleotide product.
Strand displacement amplification (Walker, G. et al., Proc. Natl.
Acad. Sci. USA 89: 392-396 (1992); U.S. Pat. Nos. 5,270,184 and
5,455,166, each of which is herein incorporated by reference in its
entirety), commonly referred to as SDA, uses cycles of annealing
pairs of primer sequences to opposite strands of a target sequence,
primer extension in the presence of a dNTP.alpha.S to produce a
duplex hemiphosphorothioated primer extension product,
endonuclease-mediated nicking of a hemimodified restriction
endonuclease recognition site, and polymerase-mediated primer
extension from the 3' end of the nick to displace an existing
strand and produce a strand for the next round of primer annealing,
nicking and strand displacement, resulting in geometric
amplification of product. Thermophilic SDA (tSDA) uses thermophilic
endonucleases and polymerases at higher temperatures in essentially
the same method (EP Pat. No. 0 684 315).
[0161] Other amplification methods include, for example: nucleic
acid sequence based amplification (U.S. Pat. No. 5,130,238, herein
incorporated by reference in its entirety), commonly referred to as
NASBA; one that uses an RNA replicase to amplify the probe molecule
itself (Lizardi et al., BioTechnol. 6: 1197 (1988), herein
incorporated by reference in its entirety), commonly referred to as
Q.beta. replicase; a transcription based amplification method (Kwoh
et al., Proc. Natl. Acad. Sci. USA 86:1173 (1989)); and,
self-sustained sequence replication (Guatelli et al., Proc. Natl.
Acad. Sci. USA 87: 1874 (1990), each of which is herein
incorporated by reference in its entirety). For further discussion
of known amplification methods see Persing, David H., "In Vitro
Nucleic Acid Amplification Techniques" in Diagnostic Medical
Microbiology: Principles and Applications (Persing et al., Eds.),
pp. 51-87 (American Society for Microbiology, Washington, D.C.
(1993)).
[0162] 4. Detection Methods
[0163] Non-amplified or amplified nucleic acids can be detected by
any conventional means. For example, the ncRNAs can be detected by
hybridization with a detectably labeled probe and measurement of
the resulting hybrids. In another example, the ncRNAs can be
detected by sequencing. Illustrative non-limiting examples of
detection methods are described herein.
[0164] One illustrative detection method, the Hybridization
Protection Assay (HPA) involves hybridizing a chemiluminescent
oligonucleotide probe (e.g., an acridinium ester-labeled (AE)
probe) to the target sequence, selectively hydrolyzing the
chemiluminescent label present on unhybridized probe, and measuring
the chemiluminescence produced from the remaining probe in a
luminometer. See, e.g., U.S. Pat. No. 5,283,174 and Norman C.
Nelson et al., Nonisotopic Probing, Blotting, and Sequencing, ch.
17 (Larry J. Kricka ed., 2d ed. 1995, each of which is herein
incorporated by reference in its entirety).
[0165] Another illustrative detection method provides for
quantitative evaluation of the amplification process in real-time.
Evaluation of an amplification process in "real-time" involves
determining the amount of amplicon in the reaction mixture either
continuously or periodically during the amplification reaction, and
using the determined values to calculate the amount of target
sequence initially present in the sample. A variety of methods for
determining the amount of initial target sequence present in a
sample based on real-time amplification are well known in the art.
These include methods disclosed in U.S. Pat. Nos. 6,303,305 and
6,541,205, each of which is herein incorporated by reference in its
entirety. Another method for determining the quantity of target
sequence initially present in a sample, but which is not based on a
real-time amplification, is disclosed in U.S. Pat. No. 5,710,029,
herein incorporated by reference in its entirety.
[0166] Amplification products may be detected in real-time through
the use of various self-hybridizing probes, most of which have a
stem-loop structure. Such self-hybridizing probes are labeled so
that they emit differently detectable signals, depending on whether
the probes are in a self-hybridized state or an altered state
through hybridization to a target sequence. By way of non-limiting
example, "molecular torches" are a type of self-hybridizing probe
that includes distinct regions of self-complementarity (referred to
as "the target binding domain" and "the target closing domain")
which are connected by a joining region (e.g., non-nucleotide
linker) and which hybridize to each other under predetermined
hybridization assay conditions. In a preferred embodiment,
molecular torches contain single-stranded base regions in the
target binding domain that are from 1 to about 20 bases in length
and are accessible for hybridization to a target sequence present
in an amplification reaction under strand displacement conditions.
Under strand displacement conditions, hybridization of the two
complementary regions, which may be fully or partially
complementary, of the molecular torch is favored, except in the
presence of the target sequence, which will bind to the
single-stranded region present in the target binding domain and
displace all or a portion of the target closing domain. The target
binding domain and the target closing domain of a molecular torch
include a detectable label or a pair of interacting labels (e.g.,
luminescent/quencher) positioned so that a different signal is
produced when the molecular torch is self-hybridized than when the
molecular torch is hybridized to the target sequence, thereby
permitting detection of probe:target duplexes in a test sample in
the presence of unhybridized molecular torches. Molecular torches
and a variety of types of interacting label pairs are disclosed in
U.S. Pat. No. 6,534,274, herein incorporated by reference in its
entirety.
[0167] Another example of a detection probe having
self-complementarity is a "molecular beacon." Molecular beacons
include nucleic acid molecules having a target complementary
sequence, an affinity pair (or nucleic acid arms) holding the probe
in a closed conformation in the absence of a target sequence
present in an amplification reaction, and a label pair that
interacts when the probe is in a closed conformation. Hybridization
of the target sequence and the target complementary sequence
separates the members of the affinity pair, thereby shifting the
probe to an open conformation. The shift to the open conformation
is detectable due to reduced interaction of the label pair, which
may be, for example, a fluorophore and a quencher (e.g., DABCYL and
EDANS). Molecular beacons are disclosed in U.S. Pat. Nos. 5,925,517
and 6,150,097, herein incorporated by reference in its
entirety.
[0168] Other self-hybridizing probes are well known to those of
ordinary skill in the art. By way of non-limiting example, probe
binding pairs having interacting labels, such as those disclosed in
U.S. Pat. No. 5,928,862 (herein incorporated by reference in its
entirety) might be adapted for use in the present invention. Probe
systems used to detect single nucleotide polymorphisms (SNPs) might
also be utilized in the present invention. Additional detection
systems include "molecular switches," as disclosed in U.S. Publ.
No. 20050042638, herein incorporated by reference in its entirety.
Other probes, such as those comprising intercalating dyes and/or
fluorochromes, are also useful for detection of amplification
products in the present invention. See, e.g., U.S. Pat. No.
5,814,447 (herein incorporated by reference in its entirety).
Additional detection methods may include microarrays and
electrophoresis (e.g., gel electrophoresis). Detection methods can
be quantitative or semi-quantitative. Detection methods may also
comprise the use of one or more labels (e.g., radioisotopes,
fluorophores, chemiluminophores, enzymes, colloidal particles, and
fluorescent microparticles, as well as antigens, antibodies,
haptens, avidin/streptavidin, biotin, haptens, or enzyme
cofactors/substrates, enzymes).
[0169] Southern and Northern blotting is used to detect specific
DNA or RNA sequences, respectively. DNA or RNA extracted from a
sample is fragmented, electrophoretically separated on a matrix
gel, and transferred to a membrane filter. The filter bound DNA or
RNA is subject to hybridization with a labeled probe complementary
to the sequence of interest. Hybridized probe bound to the filter
is detected. A variant of the procedure is the reverse Northern
blot, in which the substrate nucleic acid that is affixed to the
membrane is a collection of isolated DNA fragments and the probe is
RNA extracted from a tissue and labeled.
ii. In vivo Imaging
[0170] ncRNAs may also be detected using in vivo imaging
techniques, including but not limited to: radionuclide imaging;
positron emission tomography (PET); computerized axial tomography,
X-ray or magnetic resonance imaging method, fluorescence detection,
and chemiluminescent detection. In some embodiments, in vivo
imaging techniques are used to visualize the presence of or
expression of cancer markers in an animal (e.g., a human or
non-human mammal). For example, in some embodiments, cancer marker
mRNA or protein is labeled using a labeled antibody specific for
the cancer marker. A specifically bound and labeled antibody can be
detected in an individual using an in vivo imaging method,
including, but not limited to, radionuclide imaging, positron
emission tomography, computerized axial tomography, X-ray or
magnetic resonance imaging method, fluorescence detection, and
chemiluminescent detection. Methods for generating antibodies to
the cancer markers of the present invention are described
below.
[0171] The in vivo imaging methods of embodiments of the present
invention are useful in the identification of cancers that express
ncRNAs (e.g., prostate cancer). In vivo imaging is used to
visualize the presence or level of expression of a ncRNA. Such
techniques allow for diagnosis without the use of an unpleasant
biopsy. The in vivo imaging methods of embodiments of the present
invention can further be used to detect metastatic cancers in other
parts of the body.
[0172] In some embodiments, reagents (e.g., antibodies) specific
for the cancer markers of the present invention are fluorescently
labeled. The labeled antibodies are introduced into a subject
(e.g., orally or parenterally). Fluorescently labeled antibodies
are detected using any suitable method (e.g., using the apparatus
described in U.S. Pat. No. 6,198,107, herein incorporated by
reference).
[0173] In other embodiments, antibodies are radioactively labeled.
The use of antibodies for in vivo diagnosis is well known in the
art. Sumerdon et al., (Nucl. Med. Biol 17:247-254 [1990] have
described an optimized antibody-chelator for the
radioimmunoscintographic imaging of tumors using Indium-111 as the
label. Griffin et al., (J Clin One 9:631-640 [1991]) have described
the use of this agent in detecting tumors in patients suspected of
having recurrent colorectal cancer. The use of similar agents with
paramagnetic ions as labels for magnetic resonance imaging is known
in the art (Lauffer, Magnetic Resonance in Medicine 22:339-342
[1991]). The label used will depend on the imaging modality chosen.
Radioactive labels such as Indium-111, Technetium-99m, or
Iodine-131 can be used for planar scans or single photon emission
computed tomography (SPECT). Positron emitting labels such as
Fluorine-19 can also be used for positron emission tomography
(PET). For MRI, paramagnetic ions such as Gadolinium (III) or
Manganese (II) can be used.
[0174] Radioactive metals with half-lives ranging from 1 hour to
3.5 days are available for conjugation to antibodies, such as
scandium-47 (3.5 days) gallium-67 (2.8 days), gallium-68 (68
minutes), technetiium-99m (6 hours), and indium-111 (3.2 days), of
which gallium-67, technetium-99m, and indium-111 are preferable for
gamma camera imaging, gallium-68 is preferable for positron
emission tomography.
[0175] A useful method of labeling antibodies with such radiometals
is by means of a bifunctional chelating agent, such as
diethylenetriaminepentaacetic acid (DTPA), as described, for
example, by Khaw et al. (Science 209:295 [1980]) for In-111 and
Tc-99m, and by Scheinberg et al. (Science 215:1511 [1982]). Other
chelating agents may also be used, but the
1-(p-carboxymethoxybenzyl)EDTA and the carboxycarbonic anhydride of
DTPA are advantageous because their use permits conjugation without
affecting the antibody's immunoreactivity substantially.
[0176] Another method for coupling DPTA to proteins is by use of
the cyclic anhydride of DTPA, as described by Hnatowich et al.
(Int. J. Appl. Radiat. Isot. 33:327 [1982]) for labeling of albumin
with In-111, but which can be adapted for labeling of antibodies. A
suitable method of labeling antibodies with Tc-99m which does not
use chelation with DPTA is the pretinning method of Crockford et
al., (U.S. Pat. No. 4,323,546, herein incorporated by
reference).
[0177] A method of labeling immunoglobulins with Tc-99m is that
described by Wong et al. (Int. J. Appl. Radiat. Isot., 29:251
[1978]) for plasma protein, and recently applied successfully by
Wong et al. (J. Nucl. Med., 23:229 [1981]) for labeling
antibodies.
[0178] In the case of the radiometals conjugated to the specific
antibody, it is likewise desirable to introduce as high a
proportion of the radiolabel as possible into the antibody molecule
without destroying its immunospecificity. A further improvement may
be achieved by effecting radiolabeling in the presence of the
ncRNA, to insure that the antigen binding site on the antibody will
be protected. The antigen is separated after labeling.
[0179] In still further embodiments, in vivo biophotonic imaging
(Xenogen, Almeda, Calif.) is utilized for in vivo imaging. This
real-time in vivo imaging utilizes luciferase. The luciferase gene
is incorporated into cells, microorganisms, and animals (e.g., as a
fusion protein with a cancer marker of the present invention). When
active, it leads to a reaction that emits light. A CCD camera and
software is used to capture the image and analyze it.
[0180] iii. Data Analysis
[0181] In some embodiments, a computer-based analysis program is
used to translate the raw data generated by the detection assay
(e.g., the presence, absence, or amount of a given marker or
markers) into data of predictive value for a clinician. The
clinician can access the predictive data using any suitable means.
Thus, in some preferred embodiments, the present invention provides
the further benefit that the clinician, who is not likely to be
trained in genetics or molecular biology, need not understand the
raw data. The data is presented directly to the clinician in its
most useful form. The clinician is then able to immediately utilize
the information in order to optimize the care of the subject.
[0182] The present invention contemplates any method capable of
receiving, processing, and transmitting the information to and from
laboratories conducting the assays, information providers, medical
personnel, and subjects. For example, in some embodiments of the
present invention, a sample (e.g., a biopsy or a serum or urine
sample) is obtained from a subject and submitted to a profiling
service (e.g., clinical lab at a medical facility, genomic
profiling business, etc.), located in any part of the world (e.g.,
in a country different than the country where the subject resides
or where the information is ultimately used) to generate raw data.
Where the sample comprises a tissue or other biological sample, the
subject may visit a medical center to have the sample obtained and
sent to the profiling center, or subjects may collect the sample
themselves (e.g., a urine sample) and directly send it to a
profiling center. Where the sample comprises previously determined
biological information, the information may be directly sent to the
profiling service by the subject (e.g., an information card
containing the information may be scanned by a computer and the
data transmitted to a computer of the profiling center using an
electronic communication systems). Once received by the profiling
service, the sample is processed and a profile is produced (i.e.,
expression data), specific for the diagnostic or prognostic
information desired for the subject.
[0183] The profile data is then prepared in a format suitable for
interpretation by one or more medical personnel (e.g., a treating
clinician, physician assistant, nurse, or pharmacist). For example,
rather than providing raw expression data, the prepared format may
represent a diagnosis or risk assessment (e.g., presence or absence
of a ncRNA) for the subject, along with recommendations for
particular treatment options. The data may be displayed to the
medical personnel by any suitable method. For example, in some
embodiments, the profiling service generates a report that can be
printed for the medical personnel (e.g., at the point of care) or
displayed to the medical personnel on a computer monitor.
[0184] In some embodiments, the information is first analyzed at
the point of care or at a regional facility. The raw data is then
sent to a central processing facility for further analysis and/or
to convert the raw data to information useful for medical personnel
or patient. The central processing facility provides the advantage
of privacy (all data is stored in a central facility with uniform
security protocols), speed, and uniformity of data analysis. The
central processing facility can then control the fate of the data
following treatment of the subject. For example, using an
electronic communication system, the central facility can provide
data to the medical personnel, the subject, or researchers.
[0185] In some embodiments, the subject is able to directly access
the data using the electronic communication system. The subject may
chose further intervention or counseling based on the results.
[0186] In some embodiments, the data is used for research use. For
example, the data may be used to further optimize the inclusion or
elimination of markers as useful indicators of a particular
condition or stage of disease or as a companion diagnostic to
determine a treatment course of action.
[0187] iv. Compositions & Kits
[0188] Compositions for use in the diagnostic methods described
herein include, but are not limited to, probes, amplification
oligonucleotides, and the like.
[0189] The probe and antibody compositions of the present invention
may also be provided in the form of an array.
[0190] The compositions and kits may comprise 1 or more, 2 or more,
3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9
or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or
more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more,
40 or more, 45 or more, 50 or more, 60 or more, 70 or more, 80 or
more, 90 or more, 100 or more, 110 or more, 120 or more probes.
[0191] The probes may hybridize to 1 or more, 2 or more, 3 or more,
4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more,
10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or
more, 20 or more, 25 or more, 30 or more, 35 or more, 40 or more,
45 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or
more, 100 or more, 110 or more, 120 or more target molecules. The
target molecules may be a ncRNA, RNA, DNA, cDNA, mRNA, a portion or
fragment thereof or a combination thereof. In some instances, at
least a portion of the target molecules are ncRNAs. The probes may
hybridize to 1 or more, 2 or more, 3 or more, 4 or more, 5 or more,
6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more,
12 or more, 13 or more, 14 or more, 15 or more, 20 or more, 25 or
more, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more,
60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 110 or
more, 120 or more ncRNAs disclosed herein.
[0192] Typically, the probes comprise a target specific sequence.
The target specific sequence may be complementary to at least a
portion of the target molecule. The target specific sequence may be
at least about 50% or more, 55% or more, 60% or more, 65% or more,
70% or more, 75% or more, 80% or more, 85% or more, 90% or more,
95% or more, 97% or more, 98% or more, or 100% complementary to at
least a portion of the target molecule.
[0193] The target specific sequence may be at least about 5 or
more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or
more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more,
17 or more, 18 or more, 19 or more, 20 or more nucleotides in
length. In some instances, the target specific sequence is between
about 8 to about 20 nucleotides, 10 to about 18 nucleotides, or 12
to about 16 nucleotides in length.
[0194] The compositions and kits may comprise a plurality of
probes, wherein the two or more probes of the plurality of probes
comprise identical target specific sequences. The compositions and
kits may comprise a plurality of probes, wherein the two or more
probes of the plurality of probes comprise different target
specific sequences.
[0195] The probes may further comprise a unique sequence. The
unique sequence is noncomplementary to the ncRNA. The unique
sequence may comprise a label, barcode, or unique identifier. The
unique sequence may comprise a random sequence, nonrandom sequence,
or a combination thereof. The unique sequence may be at least about
5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more,
11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or
more, 17 or more, 18 or more, 19 or more, 20 or more, 22 or more,
24 or more, 26 or more, 28 or more, 30 or more nucleotides in
length. In some instances, the unique sequence is between about 8
to about 20 nucleotides, 10 to about 18 nucleotides, or 12 to about
16 nucleotides in length.
[0196] The unique sequence may allow differentiation of two or more
target molecules. The two or more target molecules may have
identical sequences. Thus, the unique sequence may allow
quantification of a target molecule. Alternatively, the two or more
target molecules may have different sequences. Thus, the unique
sequence may allow detection of the target molecules. The
compositions and kits may comprise a plurality of probes for
quantifying one or more target molecules. The compositions and kits
may comprise a plurality of probes for detecting one or more target
molecules.
[0197] The unique sequence may allow differentiation of two or more
samples. The compositions and kits may comprise 1 or more, 2 or
more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or
more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14
or more, 15 or more, 20 or more, 25 or more, 30 or more probe sets
for differentiating two or more samples from one or more subjects.
The two or more samples may be from two or more different subjects.
For example, the compositions and kits comprise a first set of
probes comprising a first unique sequence that is specific for a
first subject and a second set of probes comprising a second unique
sequence that is specific for a second subject. The compositions
and kits may further comprise one or more sets of probes with one
or more unique sequences to differentiate one or more additional
subjects.
[0198] The compositions and kits may comprise 2 or more probe sets
for differentiating from 2 or more, 3 or more, 4 or more, 5 or
more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or
more, 12 or more, 13 or more, 14 or more, 15 or more, 20 or more,
25 or more, 30 or more samples from 1 or more subjects.
[0199] The compositions and kits may comprise 2 or more probe sets
for differentiating 1 or more, 2 or more, 3 or more, 4 or more, 5
or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11
or more, 12 or more, 13 or more, 14 or more, 15 or more, 20 or
more, 25 or more, 30 or more samples from one or more cells,
tissues, organs, bodily fluid, or a combination thereof.
[0200] The compositions and kits may comprise 2 or more probe sets
for differentiating samples from 1 or more, 2 or more, 3 or more, 4
or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10
or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or
more, 20 or more, 25 or more, 30 or more subjects.
[0201] Alternatively, or additionally, the two or more samples may
be from two or more different timepoints from the same subject or
different subjects. For example, the compositions and kits comprise
a first set of probes comprising a first unique sequence that is
specific for a first subject and a second set of probes comprising
a second unique sequence that is specific for a second subject. The
compositions and kits may comprise 2 or more probe sets for
differentiating samples from 1 or more, 2 or more, 3 or more, 4 or
more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or
more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more,
20 or more, 25 or more, 30 or more timepoints. The timepoints may
be every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 or more hours. The timepoints may be
every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 or more days. The timepoints may be
every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 or more weeks. The timepoints may be
every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 or more months. The timepoints may be
every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24 or more years. The timepoints may be
before diagnosis, after diagnosis, before treatment, during
treatment, after treatment, before metastasis, after metastatis,
before remission, during remission, or a combination thereof.
[0202] The compositions and kits may comprise a first probe
comprising a first target-specific sequence and a first unique
sequence and a second probe comprising a second target-specific
sequence and a second unique sequence, wherein the first target
specific sequence and the second target specific sequence are
identical and the first unique sequence and the second unique
sequence are different. The compositions and kits may comprise a
first probe comprising a first target-specific sequence and a first
unique sequence and a second probe comprising a second
target-specific sequence and a second unique sequence, wherein the
first target specific sequence and the second target specific
sequence are different and the first unique sequence and the second
unique sequence are different. The compositions and kits may
comprise a first probe comprising a first target-specific sequence
and a first unique sequence and a second probe comprising a second
target-specific sequence and a second unique sequence, wherein the
first target specific sequence and the second target specific
sequence are identical and the first unique sequence and the second
unique sequence are identical. The compositions and kits may
comprise a first probe comprising a first target-specific sequence
and a first unique sequence and a second probe comprising a second
target-specific sequence and a second unique sequence, wherein the
first target specific sequence and the second target specific
sequence are different and the first unique sequence and the second
unique sequence are identical.
[0203] The probes may further comprise a universal sequence. The
universal sequence may comprise a primer binding site. The
universal sequence may enable detection of the target sequence. The
universal sequence may enable amplification of the target sequence.
The universal sequence may enable transcription or reverse
transcription of the target sequence. The universal sequence may
enable sequencing of the target sequence.
[0204] The probe and antibody compositions of the present invention
may also be provided on a solid support. The solid support may
comprise one or more beads, plates, solid surfaces, wells, chips,
or a combination thereof. The beads may be magnetic, antibody
coated, protein A crosslinked, protein G crosslinked, streptavidin
coated, oligonucleotide conjugated, silica coated, or a combination
thereof. Examples of beads include, but are not limited to, Ampure
beads, AMPure XP beads, streptavidin beads, agarose beads, magnetic
beads, Dynabeads.RTM., MACS.RTM. microbeads, antibody conjugated
beads (e.g., anti-immunoglobulin microbead), protein A conjugated
beads, protein G conjugated beads, protein A/G conjugated beads,
protein L conjugated beads, oligo-dT conjugated beads, silica
beads, silica-like beads, anti-biotin microbead, anti-fluorochrome
microbead, and BcMag.TM. Carboxy-Terminated Magnetic Beads.
[0205] The compositions and kits may comprise primers and primer
pairs capable of amplifying target molecules, or fragments or
subsequences or complements thereof. The nucleotide sequences of
the target molecules may be provided in computer-readable media for
in silico applications and as a basis for the design of appropriate
primers for amplification of one or more target molecules.
[0206] Primers based on the nucleotide sequences of target
molecules can be designed for use in amplification of the target
molecules. For use in amplification reactions such as PCR, a pair
of primers can be used. The exact composition of the primer
sequences is not critical to the invention, but for most
applications the primers may hybridize to specific sequences of the
target molecules or the universal sequence of the probe under
stringent conditions, particularly under conditions of high
stringency, as known in the art. The pairs of primers are usually
chosen so as to generate an amplification product of at least about
15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or
more, 70 or more, 80 or more, 90 or more, 100 or more, 125 or more,
150 or more, 175 or more, 200 or more, 250 or more, 300 or more,
350 or more, 400 or more, 450 or more, 500 or more, 600 or more,
700 or more, 800 or more, 900 or more, or 1000 or more nucleotides.
Algorithms for the selection of primer sequences are generally
known, and are available in commercial software packages. These
primers may be used in standard quantitative or qualitative
PCR-based assays to assess transcript expression levels of target
molecules. Alternatively, these primers may be used in combination
with probes, such as molecular beacons in amplifications using
real-time PCR.
[0207] One skilled in the art also appreciates that the nucleotide
sequence of the entire length of the primer does not need to be
derived from the target sequence. Thus, for example, the primer may
comprise nucleotide sequences at the 5' and/or 3' termini that are
not derived from the target molecule. Nucleotide sequences which
are not derived from the nucleotide sequence of the target molecule
may provide additional functionality to the primer. For example,
they may provide a restriction enzyme recognition sequence or a
"tag" that facilitates detection, isolation, purification or
immobilization onto a solid support. Alternatively, the additional
nucleotides may provide a self-complementary sequence that allows
the primer to adopt a hairpin configuration. Such configurations
may be necessary for certain primers, for example, molecular beacon
and Scorpion primers, which can be used in solution hybridization
techniques.
[0208] The probes or primers can incorporate moieties useful in
detection, isolation, purification, or immobilization, if desired.
Such moieties are well-known in the art (see, for example, Ausubel
et al., (1997 & updates) Current Protocols in Molecular
Biology, Wiley & Sons, New York) and are chosen such that the
ability of the probe to hybridize with its target molecule is not
affected.
[0209] Examples of suitable moieties are detectable labels, such as
radioisotopes, fluorophores, chemiluminophores, enzymes, colloidal
particles, and fluorescent microparticles, as well as antigens,
antibodies, haptens, avidin/streptavidin, biotin, haptens, enzyme
cofactors/substrates, enzymes, and the like.
[0210] A label can optionally be attached to or incorporated into a
probe or primer to allow detection and/or quantitation of a target
polynucleotide representing the target molecule of interest. The
target polynucleotide may be the expressed target molecule RNA
itself, a cDNA copy thereof, or an amplification product derived
therefrom, and may be the positive or negative strand, so long as
it can be specifically detected in the assay being used. Similarly,
an antibody may be labeled.
[0211] In certain multiplex formats, labels used for detecting
different target molecules may be distinguishable. The label can be
attached directly (e.g., via covalent linkage) or indirectly, e.g.,
via a bridging molecule or series of molecules (e.g., a molecule or
complex that can bind to an assay component, or via members of a
binding pair that can be incorporated into assay components, e.g.
biotin-avidin or streptavidin). Many labels are commercially
available in activated forms which can readily be used for such
conjugation (for example through amine acylation), or labels may be
attached through known or determinable conjugation schemes, many of
which are known in the art.
[0212] Labels useful in the invention described herein include any
substance which can be detected when bound to or incorporated into
the target molecule. Any effective detection method can be used,
including optical, spectroscopic, electrical, piezoelectrical,
magnetic, Raman scattering, surface plasmon resonance,
colorimetric, calorimetric, etc. A label is typically selected from
a chromophore, a lumiphore, a fluorophore, one member of a
quenching system, a chromogen, a hapten, an antigen, a magnetic
particle, a material exhibiting nonlinear optics, a semiconductor
nanocrystal, a metal nanoparticle, an enzyme, an antibody or
binding portion or equivalent thereof, an aptamer, and one member
of a binding pair, and combinations thereof. Quenching schemes may
be used, wherein a quencher and a fluorophore as members of a
quenching pair may be used on a probe, such that a change in
optical parameters occurs upon binding to the target introduce or
quench the signal from the fluorophore. One example of such a
system is a molecular beacon. Suitable quencher/fluorophore systems
are known in the art. The label may be bound through a variety of
intermediate linkages. For example, a target polynucleotide may
comprise a biotin-binding species, and an optically detectable
label may be conjugated to biotin and then bound to the labeled
target polynucleotide. Similarly, a polynucleotide sensor may
comprise an immunological species such as an antibody or fragment,
and a secondary antibody containing an optically detectable label
may be added.
[0213] Chromophores useful in the methods described herein include
any substance which can absorb energy and emit light. For
multiplexed assays, a plurality of different signaling chromophores
can be used with detectably different emission spectra. The
chromophore can be a lumophore or a fluorophore. Typical
fluorophores include fluorescent dyes, semiconductor nanocrystals,
lanthanide chelates, polynucleotide-specific dyes and green
fluorescent protein.
[0214] Coding schemes may optionally be used, comprising encoded
particles and/or encoded tags associated with different
polynucleotides of the invention. A variety of different coding
schemes are known in the art, including fluorophores, including
SCNCs, deposited metals, and RF tags.
[0215] Polynucleotides from the described target molecules may be
employed as probes for detecting target molecules expression, for
ligation amplification schemes, or may be used as primers for
amplification schemes of all or a portion of a target molecules.
When amplified, either strand produced by amplification may be
provided in purified and/or isolated form.
[0216] In some instances, the compositions and kits comprise a
biomarker library. The biomarker library may comprise 1 or more, 2
or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8
or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more,
14 or more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or
more, 40 or more, 45 or more, 50 or more, 60 or more, 70 or more,
80 or more, 90 or more, 100 or more, 110 or more, 120 or more
target molecules. The target molecules may be a ncRNA, RNA, DNA,
cDNA, mRNA, a portion or fragment thereof or a combination thereof.
In some instances, at least a portion of the target molecules are
ncRNAs. The biomarker library may comprise 1 or more, 2 or more, 3
or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9
or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or
more, 15 or more, 20 or more, 25 or more, 30 or more, 35 or more,
40 or more, 45 or more, 50 or more, 60 or more, 70 or more, 80 or
more, 90 or more, 100 or more, 110 or more, 120 or more ncRNAs
disclosed herein. The biomarker library may comprise one or more
PCATs, SChLAP-1, M41, ENST-75, TU0011194, TU0019356, TU0024146,
TU0009141, TU0062051, TU0021861, M41, ENST-75, any one of SEQ ID
NOs 1-9, or a combination thereof.
[0217] In some embodiments, is a kit for analyzing a cancer
comprising (a) a probe set comprising a plurality of probes
comprising target specific sequences complementary to one or more
target molecules, wherein the one or more target molecules comprise
one or more ncRNAs; and (b) a computer model or algorithm for
analyzing an expression level and/or expression profile of the one
or more target molecules in a sample. The target molecules may
comprise one or more PCATs, SChLAP-1, M41, ENST-75, TU0011194,
TU0019356, TU0024146, TU0009141, TU0062051, TU0021861, any one of
SEQ ID NOs 1-9, or a combination thereof.
[0218] In some embodiments, is a kit for analyzing a cancer
comprising (a) a probe set comprising a plurality of probes
comprising target specific sequences complementary to one or more
target molecules of a biomarker library; and (b) a computer model
or algorithm for analyzing an expression level and/or expression
profile of the one or more target molecules in a sample. Control
samples and/or nucleic acids may optionally be provided in the kit.
Control samples may include tissue and/or nucleic acids obtained
from or representative of tumor samples from a healthy subject, as
well as tissue and/or nucleic acids obtained from or representative
of tumor samples from subjects diagnosed with a cancer.
[0219] Instructions for using the kit to perform one or more
methods of the invention can be provided, and can be provided in
any fixed medium. The instructions may be located inside or outside
a container or housing, and/or may be printed on the interior or
exterior of any surface thereof. A kit may be in multiplex form for
concurrently detecting and/or quantitating one or more different
target polynucleotides representing the expressed target
molecules.
[0220] v. Devices
[0221] Devices useful for performing methods of the invention are
also provided. The devices can comprise means for characterizing
the expression level of a target molecule of the invention, for
example components for performing one or more methods of nucleic
acid extraction, amplification, and/or detection. Such components
may include one or more of an amplification chamber (for example a
thermal cycler), a plate reader, a spectrophotometer, capillary
electrophoresis apparatus, a chip reader, and or robotic sample
handling components. These components ultimately can obtain data
that reflects the expression level of the target molecules used in
the assay being employed.
[0222] The devices may include an excitation and/or a detection
means. Any instrument that provides a wavelength that can excite a
species of interest and is shorter than the emission wavelength(s)
to be detected can be used for excitation. Commercially available
devices can provide suitable excitation wavelengths as well as
suitable detection component.
[0223] Exemplary excitation sources include a broadband UV light
source such as a deuterium lamp with an appropriate filter, the
output of a white light source such as a xenon lamp or a deuterium
lamp after passing through a monochromator to extract out the
desired wavelength(s), a continuous wave (cw) gas laser, a solid
state diode laser, or any of the pulsed lasers. Emitted light can
be detected through any suitable device or technique; many suitable
approaches are known in the art. For example, a fluorimeter or
spectrophotometer may be used to detect whether the test sample
emits light of a wavelength characteristic of a label used in an
assay.
[0224] The devices typically comprise a means for identifying a
given sample, and of linking the results obtained to that sample.
Such means can include manual labels, barcodes, and other
indicators which can be linked to a sample vessel, and/or may
optionally be included in the sample itself, for example where an
encoded particle is added to the sample. The results may be linked
to the sample, for example in a computer memory that contains a
sample designation and a record of expression levels obtained from
the sample. Linkage of the results to the sample can also include a
linkage to a particular sample receptacle in the device, which is
also linked to the sample identity.
[0225] The devices also comprise a means for correlating the
expression levels of the target molecules being studied with a
prognosis of disease outcome. Such means may comprise one or more
of a variety of correlative techniques, including lookup tables,
algorithms, multivariate models, and linear or nonlinear
combinations of expression models or algorithms. The expression
levels may be converted to one or more likelihood scores,
reflecting a likelihood that the patient providing the sample may
exhibit a particular disease outcome. The models and/or algorithms
can be provided in machine readable format and can optionally
further designate a treatment modality for a patient or class of
patients.
[0226] The device also comprises output means for outputting the
disease status, prognosis and/or a treatment modality. Such output
means can take any form which transmits the results to a patient
and/or a healthcare provider, and may include a monitor, a printed
format, or both. The device may use a computer system for
performing one or more of the steps provided.
[0227] The methods disclosed herein may also comprise the
transmission of data/information. For example, data/information
derived from the detection and/or quantification of the target may
be transmitted to another device and/or instrument. In some
instances, the information obtained from an algorithm may also be
transmitted to another device and/or instrument. Transmission of
the data/information may comprise the transfer of data/information
from a first source to a second source. The first and second
sources may be in the same approximate location (e.g., within the
same room, building, block, campus). Alternatively, first and
second sources may be in multiple locations (e.g., multiple cities,
states, countries, continents, etc).
[0228] Transmission of the data/information may comprise digital
transmission or analog transmission. Digital transmission may
comprise the physical transfer of data (a digital bit stream) over
a point-to-point or point-to-multipoint communication channel.
Examples of such channels are copper wires, optical fibres,
wireless communication channels, and storage media. The data may be
represented as an electromagnetic signal, such as an electrical
voltage, radiowave, microwave, or infrared signal.
[0229] Analog transmission may comprise the transfer of a
continuously varying analog signal. The messages can either be
represented by a sequence of pulses by means of a line code
(baseband transmission), or by a limited set of continuously
varying wave forms (passband transmission), using a digital
modulation method. The passband modulation and corresponding
demodulation (also known as detection) can be carried out by modem
equipment. According to the most common definition of digital
signal, both baseband and passband signals representing bit-streams
are considered as digital transmission, while an alternative
definition only considers the baseband signal as digital, and
passband transmission of digital data as a form of
digital-to-analog conversion.
[0230] vii. Samples
[0231] Samples for use with the compositions and kits and in the
methods of the present invention comprise nucleic acids suitable
for providing RNA expression information. In principle, the
biological sample from which the expressed RNA is obtained and
analyzed for target molecule expression can be any material
suspected of comprising cancer tissue or cells. The sample can be a
biological sample used directly in a method of the invention.
Alternatively, the sample can be a sample prepared from a
biological sample.
[0232] In one embodiment, the sample or portion of the sample
comprising or suspected of comprising cancer tissue or cells can be
any source of biological material, including cells, tissue,
secretions, or fluid, including bodily fluids. Non-limiting
examples of the source of the sample include an aspirate, a needle
biopsy, a cytology pellet, a bulk tissue preparation or a section
thereof obtained for example by surgery or autopsy, lymph fluid,
blood, plasma, serum, tumors, and organs. Alternatively, or
additionally, the source of the sample can be urine, bile,
excrement, sweat, tears, vaginal fluids, spinal fluid, and stool.
In some instances, the sources of the sample are secretions. In
some instances, the secretions are exosomes.
[0233] The samples may be archival samples, having a known and
documented medical outcome, or may be samples from current patients
whose ultimate medical outcome is not yet known.
[0234] In some embodiments, the sample may be dissected prior to
molecular analysis. The sample may be prepared via macrodissection
of a bulk tumor specimen or portion thereof, or may be treated via
microdissection, for example via Laser Capture Microdissection
(LCM).
[0235] The sample may initially be provided in a variety of states,
as fresh tissue, fresh frozen tissue, fine needle aspirates, and
may be fixed or unfixed. Frequently, medical laboratories routinely
prepare medical samples in a fixed state, which facilitates tissue
storage. A variety of fixatives can be used to fix tissue to
stabilize the morphology of cells, and may be used alone or in
combination with other agents. Exemplary fixatives include
crosslinking agents, alcohols, acetone, Bouin's solution, Zenker
solution, Hely solution, osmic acid solution and Carnoy
solution.
[0236] Crosslinking fixatives can comprise any agent suitable for
forming two or more covalent bonds, for example, an aldehyde.
Sources of aldehydes typically used for fixation include
formaldehyde, paraformaldehyde, glutaraldehyde or formalin.
Preferably, the crosslinking agent comprises formaldehyde, which
may be included in its native form or in the form of
paraformaldehyde or formalin. One of skill in the art would
appreciate that for samples in which crosslinking fixatives have
been used special preparatory steps may be necessary including for
example heating steps and proteinase-k digestion.
[0237] One or more alcohols may be used to fix tissue, alone or in
combination with other fixatives. Exemplary alcohols used for
fixation include methanol, ethanol and isopropanol.
[0238] Formalin fixation is frequently used in medical
laboratories. Formalin comprises both an alcohol, typically
methanol, and formaldehyde, both of which can act to fix a
biological sample.
[0239] Whether fixed or unfixed, the biological sample may
optionally be embedded in an embedding medium. Exemplary embedding
media used in histology including paraffin, Tissue-Tek.RTM.
V.I.P..TM., Paramat, Paramat Extra, Paraplast, Paraplast X-tra,
Paraplast Plus, Peel Away Paraffin Embedding Wax, Polyester Wax,
Carbowax Polyethylene Glycol, Polyfin.TM., Tissue Freezing Medium
TFMFM, Cryo-Gef.TM., and OCT Compound (Electron Microscopy
Sciences, Hatfield, Pa.). Prior to molecular analysis, the
embedding material may be removed via any suitable techniques, as
known in the art. For example, where the sample is embedded in wax,
the embedding material may be removed by extraction with organic
solvent(s), for example xylenes. Kits are commercially available
for removing embedding media from tissues. Samples or sections
thereof may be subjected to further processing steps as needed, for
example serial hydration or dehydration steps.
[0240] In some embodiments, the sample is a fixed, wax-embedded
biological sample. Frequently, samples from medical laboratories
are provided as fixed, wax-embedded samples, most commonly as
formalin-fixed, paraffin embedded (FFPE) tissues.
[0241] Whatever the source of the biological sample, the target
polynucleotide that is ultimately assayed can be prepared
synthetically (in the case of control sequences), but typically is
purified from the biological source and subjected to one or more
preparative steps. The RNA may be purified to remove or diminish
one or more undesired components from the biological sample or to
concentrate it. Conversely, where the RNA is too concentrated for
the particular assay, it may be diluted.
II. Drug Screening Applications
[0242] In some embodiments, the present invention provides drug
screening assays (e.g., to screen for anticancer drugs). The
screening methods of the present invention utilize ncRNAs. For
example, in some embodiments, the present invention provides
methods of screening for compounds that alter the expression or
activity of ncRNAs. The compounds may increase the expression or
activity of the ncRNAs. The compounds may decrease the expression
or activity of the ncRNAs. The compounds or agents may interfere
with transcription, by interacting, for example, with the promoter
region. The compounds or agents may interfere with mRNA (e.g., by
RNA interference, antisense technologies, etc.). The compounds or
agents may interfere with pathways that are upstream or downstream
of the biological activity of ncRNAs. In some embodiments,
candidate compounds are antisense or interfering RNA agents (e.g.,
oligonucleotides) directed against ncRNAs. In other embodiments,
candidate compounds are antibodies or small molecules that
specifically bind to a ncRNA regulator. Alternatively, or
additionally, the candidate compounds are expression products that
inhibit the biological function of the ncRNAs.
[0243] In one screening method, candidate compounds are evaluated
for their ability to alter ncRNAs expression by contacting a
compound with a cell expressing a ncRNA and then assaying for the
effect of the candidate compounds on expression. In some
embodiments, the effect of candidate compounds on expression of
ncRNAs is assayed for by detecting the level ncRNA expressed by the
cell. mRNA expression can be detected by any suitable method.
III. Diagnosis, Prognosis, and Monitoring
[0244] The methods, compositions, and kits disclosed herein may be
used for the diagnosis, prognosis, and/or monitoring the status or
outcome of a cancer in a subject. In some embodiments, the
diagnosing, predicting, and/or monitoring the status or outcome of
a cancer comprises determining the malignancy or malignant
potential of the cancer or tumor. Alternatively, the diagnosing,
predicting, and/or monitoring the status or outcome of a cancer
comprises determining the stage of the cancer. The diagnosing,
predicting, and/or monitoring the status or outcome of a cancer can
comprise determining the tumor grade. Alternatively, the
diagnosing, predicting, and/or monitoring the status or outcome of
a cancer comprises assessing the risk of developing a cancer. In
some embodiments, the diagnosing, predicting, and/or monitoring the
status or outcome of a cancer includes assessing the risk of cancer
recurrence. In some embodiments, diagnosing, predicting, and/or
monitoring the status or outcome of a cancer may comprise
determining the efficacy of treatment.
[0245] In some embodiments, diagnosing, predicting, and/or
monitoring the status or outcome of a cancer may comprise
determining a therapeutic regimen. Determining a therapeutic
regimen may comprise administering an anti-cancer therapeutic.
Alternatively, determining the treatment for the cancer may
comprise modifying a therapeutic regimen. Modifying a therapeutic
regimen may comprise increasing, decreasing, or terminating a
therapeutic regimen.
[0246] In some instances, the methods disclosed herein can
diagnose, prognose, and/or monitor the status or outcome of a
cancer in a subject with an accuracy of at least about 50%. In
other instances, the methods disclosed herein can diagnose,
prognose, and/or monitor the status or outcome of a cancer in a
subject with an accuracy of at least about 60%. The methods
disclosed herein can diagnose, prognose, and/or monitor the status
or outcome of a cancer in a subject with an accuracy of at least
about 65%. Alternatively, the methods disclosed herein can
diagnose, prognose, and/or monitor the status or outcome of a
cancer in a subject with an accuracy of at least about 70%. In some
instances, the methods disclosed herein can diagnose, prognose,
and/or monitor the status or outcome of a cancer in a subject with
an accuracy of at least about 75%. In other instances, the methods
disclosed herein can diagnose, prognose, and/or monitor the status
or outcome of a cancer in a subject with an accuracy of at least
about 80%. The methods disclosed herein can diagnose, prognose,
and/or monitor the status or outcome of a cancer in a subject with
an accuracy of at least about 85%. Alternatively, the methods
disclosed herein can diagnose, prognose, and/or monitor the status
or outcome of a cancer in a subject with an accuracy of at least
about 90%. The methods disclosed herein can diagnose, prognose,
and/or monitor the status or outcome of a cancer in a subject with
an accuracy of at least about 95%.
[0247] The invention also encompasses any of the methods disclosed
herein where the sensitivity is at least about 45%. In some
embodiments, the sensitivity is at least about 50%. In some
embodiments, the sensitivity is at least about 55%. In some
embodiments, the sensitivity is at least about 60%. In some
embodiments, the sensitivity is at least about 65%. In some
embodiments, the sensitivity is at least about 70%. In some
embodiments, the sensitivity is at least about 75%. In some
embodiments, the sensitivity is at least about 80%. In some
embodiments, the sensitivity is at least about 85%. In some
embodiments, the sensitivity is at least about 90%. In some
embodiments, the sensitivity is at least about 95%.
[0248] The invention also encompasses any of the methods disclosed
herein where the expression level determines the status or outcome
of a cancer in the subject with at least about 45% specificity. In
some embodiments, the expression level determines the status or
outcome of a cancer in the subject with at least about 50%
specificity. In some embodiments, the expression level determines
the status or outcome of a cancer in the subject with at least
about 55% specificity. In some embodiments, the expression level
determines the status or outcome of a cancer in the subject with at
least about 60% specificity. In some embodiments, the expression
level determines the status or outcome of a cancer in the subject
with at least about 65% specificity. In some embodiments, the
expression level determines the status or outcome of a cancer in
the subject with at least about 70% specificity. In some
embodiments, the expression level determines the status or outcome
of a cancer in the subject with at least about 75% specificity. In
some embodiments, the expression level determines the status or
outcome of a cancer in the subject with at least about 80%
specificity. In some embodiments, the expression level determines
the status or outcome of a cancer in the subject with at least
about 85% specificity. In some embodiments, the expression level
determines the status or outcome of a cancer in the subject with at
least about 90% specificity. In some embodiments, the expression
level determines the status or outcome of a cancer in the subject
with at least about 95% specificity.
[0249] Cancer
[0250] The systems, compositions and methods disclosed herein may
be used to diagnosis, monitor and/or predict the status or outcome
of a cancer. Generally, a cancer is characterized by the
uncontrolled growth of abnormal cells anywhere in a body. The
abnormal cells may be termed cancer cells, malignant cells, or
tumor cells. Many cancers and the abnormal cells that compose the
cancer tissue are further identified by the name of the tissue that
the abnormal cells originated from (for example, breast cancer,
lung cancer, colon cancer, prostate cancer, pancreatic cancer,
thyroid cancer). Cancer is not confined to humans; animals and
other living organisms can get cancer.
[0251] In some instances, the cancer may be malignant.
Alternatively, the cancer may be benign. The cancer may be a
recurrent and/or refractory cancer. Most cancers can be classified
as a carcinoma, sarcoma, leukemia, lymphoma, myeloma, or a central
nervous system cancer.
[0252] The cancer may be a sarcoma. Sarcomas are cancers of the
bone, cartilage, fat, muscle, blood vessels, or other connective or
supportive tissue. Sarcomas include, but are not limited to, bone
cancer, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant
hemangioendothelioma, malignant schwannoma, bilateral vestibular
schwannoma, osteosarcoma, soft tissue sarcomas (e.g. alveolar soft
part sarcoma, angiosarcoma, cystosarcoma phylloides,
dermatofibrosarcoma, desmoid tumor, epithelioid sarcoma,
extraskeletal osteosarcoma, fibrosarcoma, hemangiopericytoma,
hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,
lymphangiosarcoma, lymphosarcoma, malignant fibrous histiocytoma,
neurofibrosarcoma, rhabdomyosarcoma, and synovial sarcoma).
[0253] Alternatively, the cancer may be a carcinoma. Carcinomas are
cancers that begin in the epithelial cells, which are cells that
cover the surface of the body, produce hormones, and make up
glands. By way of non-limiting example, carcinomas include breast
cancer, pancreatic cancer, lung cancer, colon cancer, colorectal
cancer, rectal cancer, kidney cancer, bladder cancer, stomach
cancer, prostate cancer, liver cancer, ovarian cancer, brain
cancer, vaginal cancer, vulvar cancer, uterine cancer, oral cancer,
penic cancer, testicular cancer, esophageal cancer, skin cancer,
cancer of the fallopian tubes, head and neck cancer,
gastrointestinal stromal cancer, adenocarcinoma, cutaneous or
intraocular melanoma, cancer of the anal region, cancer of the
small intestine, cancer of the endocrine system, cancer of the
thyroid gland, cancer of the parathyroid gland, cancer of the
adrenal gland, cancer of the urethra, cancer of the renal pelvis,
cancer of the ureter, cancer of the endometrium, cancer of the
cervix, cancer of the pituitary gland, neoplasms of the central
nervous system (CNS), primary CNS lymphoma, brain stem glioma, and
spinal axis tumors. In some instances, the cancer is a skin cancer,
such as a basal cell carcinoma, squamous, melanoma, nonmelanoma, or
actinic (solar) keratosis. Preferably, the cancer is a prostate
cancer. Alternatively, the cancer may be a thyroid cancer. The
cancer can be a pancreatic cancer. In some instances, the cancer is
a bladder cancer.
[0254] In some instances, the cancer is a lung cancer. Lung cancer
can start in the airways that branch off the trachea to supply the
lungs (bronchi) or the small air sacs of the lung (the alveoli).
Lung cancers include non-small cell lung carcinoma (NSCLC), small
cell lung carcinoma, and mesotheliomia. Examples of NSCLC include
squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
The mesothelioma may be a cancerous tumor of the lining of the lung
and chest cavity (pleura) or lining of the abdomen (peritoneum).
The mesothelioma may be due to asbestos exposure. The cancer may be
a brain cancer, such as a glioblastoma.
[0255] Alternatively, the cancer may be a central nervous system
(CNS) tumor. CNS tumors may be classified as gliomas or nongliomas.
The glioma may be malignant glioma, high grade glioma, diffuse
intrinsic pontine glioma. Examples of gliomas include astrocytomas,
oligodendrogliomas (or mixtures of oligodendroglioma and astocytoma
elements), and ependymomas. Astrocytomas include, but are not
limited to, low-grade astrocytomas, anaplastic astrocytomas,
glioblastoma multiforme, pilocytic astrocytoma, pleomorphic
xanthoastrocytoma, and subependymal giant cell astrocytoma.
Oligodendrogliomas include low-grade oligodendrogliomas (or
oligoastrocytomas) and anaplastic oligodendriogliomas. Nongliomas
include meningiomas, pituitary adenomas, primary CNS lymphomas, and
medulloblastomas. In some instances, the cancer is a
meningioma.
[0256] The cancer may be leukemia. The leukemia may be an acute
lymphocytic leukemia, acute myelocytic leukemia, chronic
lymphocytic leukemia, or chronic myelocytic leukemia. Additional
types of leukemias include hairy cell leukemia, chronic
myelomonocytic leukemia, and juvenile myelomonocytic-leukemia.
[0257] In some instances, the cancer is a lymphoma. Lymphomas are
cancers of the lymphocytes and may develop from either B or T
lymphocytes. The two major types of lymphoma are Hodgkin's
lymphoma, previously known as Hodgkin's disease, and non-Hodgkin's
lymphoma. Hodgkin's lymphoma is marked by the presence of the
Reed-Sternberg cell. Non-Hodgkin's lymphomas are all lymphomas
which are not Hodgkin's lymphoma. Non-Hodgkin lymphomas may be
indolent lymphomas and aggressive lymphomas. Non-Hodgkin's
lymphomas include, but are not limited to, diffuse large B cell
lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue
lymphoma (MALT), small cell lymphocytic lymphoma, mantle cell
lymphoma, Burkitt's lymphoma, mediastinal large B cell lymphoma,
Waldenstrom macroglobulinemia, nodal marginal zone B cell lymphoma
(NMZL), splenic marginal zone lymphoma (SMZL), extranodal marginal
zone B cell lymphoma, intravascular large B cell lymphoma, primary
effusion lymphoma, and lymphomatoid granulomatosis.
[0258] Cancer Staging
[0259] Diagnosing, predicting, or monitoring a status or outcome of
a cancer may comprise determining the stage of the cancer.
Generally, the stage of a cancer is a description (usually numbers
I to IV with IV having more progression) of the extent the cancer
has spread. The stage often takes into account the size of a tumor,
how deeply it has penetrated, whether it has invaded adjacent
organs, how many lymph nodes it has metastasized to (if any), and
whether it has spread to distant organs. Staging of cancer can be
used as a predictor of survival, and cancer treatment may be
determined by staging. Determining the stage of the cancer may
occur before, during, or after treatment. The stage of the cancer
may also be determined at the time of diagnosis.
[0260] Cancer staging can be divided into a clinical stage and a
pathologic stage. Cancer staging may comprise the TNM
classification. Generally, the TNM Classification of Malignant
Tumours (TNM) is a cancer staging system that describes the extent
of cancer in a patient's body. T may describe the size of the tumor
and whether it has invaded nearby tissue, N may describe regional
lymph nodes that are involved, and M may describe distant
metastasis (spread of cancer from one body part to another). In the
TNM (Tumor, Node, Metastasis) system, clinical stage and pathologic
stage are denoted by a small "c" or "p" before the stage (e.g.,
cT3N1M0 or pT2N0).
[0261] Often, clinical stage and pathologic stage may differ.
Clinical stage may be based on all of the available information
obtained before a surgery to remove the tumor. Thus, it may include
information about the tumor obtained by physical examination,
radiologic examination, and endoscopy. Pathologic stage can add
additional information gained by examination of the tumor
microscopically by a pathologist. Pathologic staging can allow
direct examination of the tumor and its spread, contrasted with
clinical staging which may be limited by the fact that the
information is obtained by making indirect observations at a tumor
which is still in the body. The TNM staging system can be used for
most forms of cancer.
[0262] Alternatively, staging may comprise Ann Arbor staging.
Generally, Ann Arbor staging is the staging system for lymphomas,
both in Hodgkin's lymphoma (previously called Hodgkin's disease)
and Non-Hodgkin lymphoma (abbreviated NHL). The stage may depend on
both the place where the malignant tissue is located (as located
with biopsy, CT scanning and increasingly positron emission
tomography) and on systemic symptoms due to the lymphoma ("B
symptoms": night sweats, weight loss of >10% or fevers). The
principal stage may be determined by location of the tumor. Stage I
may indicate that the cancer is located in a single region, usually
one lymph node and the surrounding area. Stage I often may not have
outward symptoms. Stage II can indicate that the cancer is located
in two separate regions, an affected lymph node or organ and a
second affected area, and that both affected areas are confined to
one side of the diaphragm--that is, both are above the diaphragm,
or both are below the diaphragm. Stage III often indicates that the
cancer has spread to both sides of the diaphragm, including one
organ or area near the lymph nodes or the spleen. Stage IV may
indicate diffuse or disseminated involvement of one or more
extralymphatic organs, including any involvement of the liver, bone
marrow, or nodular involvement of the lungs.
[0263] Modifiers may also be appended to some stages. For example,
the letters A, B, E, X, or S can be appended to some stages.
Generally, A or B may indicate the absence of constitutional
(B-type) symptoms is denoted by adding an "A" to the stage; the
presence is denoted by adding a "B" to the stage. E can be used if
the disease is "extranodal" (not in the lymph nodes) or has spread
from lymph nodes to adjacent tissue. X is often used if the largest
deposit is >10 cm large ("bulky disease"), or whether the
mediastinum is wider than 1/3 of the chest on a chest X-ray. S may
be used if the disease has spread to the spleen.
[0264] The nature of the staging may be expressed with CS or PS. CS
may denote that the clinical stage as obtained by doctor's
examinations and tests. PS may denote that the pathological stage
as obtained by exploratory laparotomy (surgery performed through an
abdominal incision) with splenectomy (surgical removal of the
spleen).
[0265] Therapeutic Regimens
[0266] Diagnosing, predicting, or monitoring a status or outcome of
a cancer may comprise treating a cancer or preventing a cancer
progression. In addition, diagnosing, predicting, or monitoring a
status or outcome of a cancer may comprise identifying or
predicting responders to an anti-cancer therapy. In some instances,
diagnosing, predicting, or monitoring may comprise determining a
therapeutic regimen. Determining a therapeutic regimen may comprise
administering an anti-cancer therapy. Alternatively, determining a
therapeutic regimen may comprise modifying, recommending,
continuing or discontinuing an anti-cancer regimen. In some
instances, if the sample expression patterns are consistent with
the expression pattern for a known disease or disease outcome, the
expression patterns can be used to designate one or more treatment
modalities (e.g., therapeutic regimens, anti-cancer regimen). An
anti-cancer regimen may comprise one or more anti-cancer therapies.
Examples of anti-cancer therapies include surgery, chemotherapy,
radiation therapy, immunotherapy/biological therapy, photodynamic
therapy.
[0267] Surgical oncology uses surgical methods to diagnose, stage,
and treat cancer, and to relieve certain cancer-related symptoms.
Surgery may be used to remove the tumor (e.g., excisions,
resections, debulking surgery), reconstruct a part of the body
(e.g., restorative surgery), and/or to relieve symptoms such as
pain (e.g., palliative surgery). Surgery may also include
cryosurgery. Cryosurgery (also called cryotherapy) may use extreme
cold produced by liquid nitrogen (or argon gas) to destroy abnormal
tissue. Cryosurgery can be used to treat external tumors, such as
those on the skin. For external tumors, liquid nitrogen can be
applied directly to the cancer cells with a cotton swab or spraying
device. Cryosurgery may also be used to treat tumors inside the
body (internal tumors and tumors in the bone). For internal tumors,
liquid nitrogen or argon gas may be circulated through a hollow
instrument called a cryoprobe, which is placed in contact with the
tumor. An ultrasound or MRI may be used to guide the cryoprobe and
monitor the freezing of the cells, thus limiting damage to nearby
healthy tissue. A ball of ice crystals may form around the probe,
freezing nearby cells. Sometimes more than one probe is used to
deliver the liquid nitrogen to various parts of the tumor. The
probes may be put into the tumor during surgery or through the skin
(percutaneously). After cryosurgery, the frozen tissue thaws and
may be naturally absorbed by the body (for internal tumors), or may
dissolve and form a scab (for external tumors).
[0268] Chemotherapeutic agents may also be used for the treatment
of cancer. Examples of chemotherapeutic agents include alkylating
agents, anti-metabolites, plant alkaloids and terpenoids, vinca
alkaloids, podophyllotoxin, taxanes, topoisomerase inhibitors, and
cytotoxic antibiotics. Cisplatin, carboplatin, and oxaliplatin are
examples of alkylating agents. Other alkylating agents include
mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide.
Alkylating agents may impair cell function by forming covalent
bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in
biologically important molecules. Alternatively, alkylating agents
may chemically modify a cell's DNA.
[0269] Anti-metabolites are another example of chemotherapeutic
agents. Anti-metabolites may masquerade as purines or pyrimidines
and may prevent purines and pyrimidines from becoming incorporated
in to DNA during the "S" phase (of the cell cycle), thereby
stopping normal development and division. Antimetabolites may also
affect RNA synthesis. Examples of metabolites include azathioprine
and mercaptopurine.
[0270] Alkaloids may be derived from plants and block cell division
may also be used for the treatment of cancer. Alkyloids may prevent
microtubule function. Examples of alkaloids are vinca alkaloids and
taxanes. Vinca alkaloids may bind to specific sites on tubulin and
inhibit the assembly of tubulin into microtubules (M phase of the
cell cycle). The vinca alkaloids may be derived from the Madagascar
periwinkle, Catharanthus roseus (formerly known as Vinca rosea).
Examples of vinca alkaloids include, but are not limited to,
vincristine, vinblastine, vinorelbine, or vindesine. Taxanes are
diterpenes produced by the plants of the genus Taxus (yews).
Taxanes may be derived from natural sources or synthesized
artificially. Taxanes include paclitaxel (Taxol) and docetaxel
(Taxotere). Taxanes may disrupt microtubule function. Microtubules
are essential to cell division, and taxanes may stabilize GDP-bound
tubulin in the microtubule, thereby inhibiting the process of cell
division. Thus, in essence, taxanes may be mitotic inhibitors.
Taxanes may also be radiosensitizing and often contain numerous
chiral centers.
[0271] Alternative chemotherapeutic agents include podophyllotoxin.
Podophyllotoxin is a plant-derived compound that may help with
digestion and may be used to produce cytostatic drugs such as
etoposide and teniposide. They may prevent the cell from entering
the G1 phase (the start of DNA replication) and the replication of
DNA (the S phase).
[0272] Topoisomerases are essential enzymes that maintain the
topology of DNA. Inhibition of type I or type II topoisomerases may
interfere with both transcription and replication of DNA by
upsetting proper DNA supercoiling. Some chemotherapeutic agents may
inhibit topoisomerases. For example, some type I topoisomerase
inhibitors include camptothecins: irinotecan and topotecan.
Examples of type II inhibitors include amsacrine, etoposide,
etoposide phosphate, and teniposide.
[0273] Another example of chemotherapeutic agents is cytotoxic
antibiotics. Cytotoxic antibiotics are a group of antibiotics that
are used for the treatment of cancer because they may interfere
with DNA replication and/or protein synthesis. Cytotoxic
antiobiotics include, but are not limited to, actinomycin,
anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin,
epirubicin, bleomycin, plicamycin, and mitomycin.
[0274] In some instances, the anti-cancer treatment may comprise
radiation therapy. Radiation can come from a machine outside the
body (external-beam radiation therapy) or from radioactive material
placed in the body near cancer cells (internal radiation therapy,
more commonly called brachytherapy). Systemic radiation therapy
uses a radioactive substance, given by mouth or into a vein that
travels in the blood to tissues throughout the body.
[0275] External-beam radiation therapy may be delivered in the form
of photon beams (either x-rays or gamma rays). A photon is the
basic unit of light and other forms of electromagnetic radiation.
An example of external-beam radiation therapy is called
3-dimensional conformal radiation therapy (3D-CRT). 3D-CRT may use
computer software and advanced treatment machines to deliver
radiation to very precisely shaped target areas. Many other methods
of external-beam radiation therapy are currently being tested and
used in cancer treatment. These methods include, but are not
limited to, intensity-modulated radiation therapy (IMRT),
image-guided radiation therapy (IGRT), Stereotactic radiosurgery
(SRS), Stereotactic body radiation therapy (SBRT), and proton
therapy.
[0276] Intensity-modulated radiation therapy (IMRT) is an example
of external-beam radiation and may use hundreds of tiny radiation
beam-shaping devices, called collimators, to deliver a single dose
of radiation. The collimators can be stationary or can move during
treatment, allowing the intensity of the radiation beams to change
during treatment sessions. This kind of dose modulation allows
different areas of a tumor or nearby tissues to receive different
doses of radiation. IMRT is planned in reverse (called inverse
treatment planning). In inverse treatment planning, the radiation
doses to different areas of the tumor and surrounding tissue are
planned in advance, and then a high-powered computer program
calculates the required number of beams and angles of the radiation
treatment. In contrast, during traditional (forward) treatment
planning, the number and angles of the radiation beams are chosen
in advance and computers calculate how much dose may be delivered
from each of the planned beams. The goal of IMRT is to increase the
radiation dose to the areas that need it and reduce radiation
exposure to specific sensitive areas of surrounding normal
tissue.
[0277] Another example of external-beam radiation is image-guided
radiation therapy (IGRT). In IGRT, repeated imaging scans (CT, MRI,
or PET) may be performed during treatment. These imaging scans may
be processed by computers to identify changes in a tumor's size and
location due to treatment and to allow the position of the patient
or the planned radiation dose to be adjusted during treatment as
needed. Repeated imaging can increase the accuracy of radiation
treatment and may allow reductions in the planned volume of tissue
to be treated, thereby decreasing the total radiation dose to
normal tissue.
[0278] Tomotherapy is a type of image-guided IMRT. A tomotherapy
machine is a hybrid between a CT imaging scanner and an
external-beam radiation therapy machine. The part of the
tomotherapy machine that delivers radiation for both imaging and
treatment can rotate completely around the patient in the same
manner as a normal CT scanner. Tomotherapy machines can capture CT
images of the patient's tumor immediately before treatment
sessions, to allow for very precise tumor targeting and sparing of
normal tissue.
[0279] Stereotactic radiosurgery (SRS) can deliver one or more high
doses of radiation to a small tumor. SRS uses extremely accurate
image-guided tumor targeting and patient positioning. Therefore, a
high dose of radiation can be given without excess damage to normal
tissue. SRS can be used to treat small tumors with well-defined
edges. It is most commonly used in the treatment of brain or spinal
tumors and brain metastases from other cancer types. For the
treatment of some brain metastases, patients may receive radiation
therapy to the entire brain (called whole-brain radiation therapy)
in addition to SRS. SRS requires the use of a head frame or other
device to immobilize the patient during treatment to ensure that
the high dose of radiation is delivered accurately.
[0280] Stereotactic body radiation therapy (SBRT) delivers
radiation therapy in fewer sessions, using smaller radiation fields
and higher doses than 3D-CRT in most cases. SBRT may treat tumors
that lie outside the brain and spinal cord. Because these tumors
are more likely to move with the normal motion of the body, and
therefore cannot be targeted as accurately as tumors within the
brain or spine, SBRT is usually given in more than one dose. SBRT
can be used to treat small, isolated tumors, including cancers in
the lung and liver. SBRT systems may be known by their brand names,
such as the CyberKnife.RTM..
[0281] In proton therapy, external-beam radiation therapy may be
delivered by proton. Protons are a type of charged particle. Proton
beams differ from photon beams mainly in the way they deposit
energy in living tissue. Whereas photons deposit energy in small
packets all along their path through tissue, protons deposit much
of their energy at the end of their path (called the Bragg peak)
and deposit less energy along the way. Use of protons may reduce
the exposure of normal tissue to radiation, possibly allowing the
delivery of higher doses of radiation to a tumor.
[0282] Other charged particle beams such as electron beams may be
used to irradiate superficial tumors, such as skin cancer or tumors
near the surface of the body, but they cannot travel very far
through tissue.
[0283] Internal radiation therapy (brachytherapy) is radiation
delivered from radiation sources (radioactive materials) placed
inside or on the body. Several brachytherapy techniques are used in
cancer treatment. Interstitial brachytherapy may use a radiation
source placed within tumor tissue, such as within a prostate tumor.
Intracavitary brachytherapy may use a source placed within a
surgical cavity or a body cavity, such as the chest cavity, near a
tumor. Episcleral brachytherapy, which may be used to treat
melanoma inside the eye, may use a source that is attached to the
eye. In brachytherapy, radioactive isotopes can be sealed in tiny
pellets or "seeds." These seeds may be placed in patients using
delivery devices, such as needles, catheters, or some other type of
carrier. As the isotopes decay naturally, they give off radiation
that may damage nearby cancer cells. Brachytherapy may be able to
deliver higher doses of radiation to some cancers than
external-beam radiation therapy while causing less damage to normal
tissue.
[0284] Brachytherapy can be given as a low-dose-rate or a
high-dose-rate treatment. In low-dose-rate treatment, cancer cells
receive continuous low-dose radiation from the source over a period
of several days. In high-dose-rate treatment, a robotic machine
attached to delivery tubes placed inside the body may guide one or
more radioactive sources into or near a tumor, and then removes the
sources at the end of each treatment session. High-dose-rate
treatment can be given in one or more treatment sessions. An
example of a high-dose-rate treatment is the MammoSite.RTM. system.
Bracytherapy may be used to treat patients with breast cancer who
have undergone breast-conserving surgery.
[0285] The placement of brachytherapy sources can be temporary or
permanent. For permanent brachytherapy, the sources may be
surgically sealed within the body and left there, even after all of
the radiation has been given off. In some instances, the remaining
material (in which the radioactive isotopes were sealed) does not
cause any discomfort or harm to the patient. Permanent
brachytherapy is a type of low-dose-rate brachytherapy. For
temporary brachytherapy, tubes (catheters) or other carriers are
used to deliver the radiation sources, and both the carriers and
the radiation sources are removed after treatment. Temporary
brachytherapy can be either low-dose-rate or high-dose-rate
treatment. Brachytherapy may be used alone or in addition to
external-beam radiation therapy to provide a "boost" of radiation
to a tumor while sparing surrounding normal tissue.
[0286] In systemic radiation therapy, a patient may swallow or
receive an injection of a radioactive substance, such as
radioactive iodine or a radioactive substance bound to a monoclonal
antibody. Radioactive iodine (131I) is a type of systemic radiation
therapy commonly used to help treat cancer, such as thyroid cancer.
Thyroid cells naturally take up radioactive iodine. For systemic
radiation therapy for some other types of cancer, a monoclonal
antibody may help target the radioactive substance to the right
place. The antibody joined to the radioactive substance travels
through the blood, locating and killing tumor cells. For example,
the drug ibritumomab tiuxetan (Zevalin.RTM.) may be used for the
treatment of certain types of B-cell non-Hodgkin lymphoma (NHL).
The antibody part of this drug recognizes and binds to a protein
found on the surface of B lymphocytes. The combination drug regimen
of tositumomab and iodine I 131 tositumomab (Bexxar.RTM.) may be
used for the treatment of certain types of cancer, such as NHL. In
this regimen, nonradioactive tositumomab antibodies may be given to
patients first, followed by treatment with tositumomab antibodies
that have 131I attached. Tositumomab may recognize and bind to the
same protein on B lymphocytes as ibritumomab. The nonradioactive
form of the antibody may help protect normal B lymphocytes from
being damaged by radiation from 131I.
[0287] Some systemic radiation therapy drugs relieve pain from
cancer that has spread to the bone (bone metastases). This is a
type of palliative radiation therapy. The radioactive drugs
samarium-153-lexidronam (Quadramet.RTM.) and strontium-89 chloride
(Metastron.RTM.) are examples of radiopharmaceuticals may be used
to treat pain from bone metastases.
[0288] Biological therapy (sometimes called immunotherapy,
biotherapy, or biological response modifier (BRM) therapy) uses the
body's immune system, either directly or indirectly, to fight
cancer or to lessen the side effects that may be caused by some
cancer treatments. Biological therapies include interferons,
interleukins, colony-stimulating factors, monoclonal antibodies,
vaccines, gene therapy, and nonspecific immunomodulating
agents.
[0289] Interferons (IFNs) are types of cytokines that occur
naturally in the body. Interferon alpha, interferon beta, and
interferon gamma are examples of interferons that may be used in
cancer treatment.
[0290] Like interferons, interleukins (ILs) are cytokines that
occur naturally in the body and can be made in the laboratory. Many
interleukins have been identified for the treatment of cancer. For
example, interleukin-2 (IL-2 or aldesleukin), interleukin 7, and
interleukin 12 have may be used as an anti-cancer treatment. IL-2
may stimulate the growth and activity of many immune cells, such as
lymphocytes, that can destroy cancer cells. Interleukins may be
used to treat a number of cancers, including leukemia, lymphoma,
and brain, colorectal, ovarian, breast, kidney and prostate
cancers.
[0291] Colony-stimulating factors (CSFs) (sometimes called
hematopoietic growth factors) may also be used for the treatment of
cancer. Some examples of CSFs include, but are not limited to,
G-CSF (filgrastim) and GM-CSF (sargramostim). CSFs may promote the
division of bone marrow stem cells and their development into white
blood cells, platelets, and red blood cells. Bone marrow is
critical to the body's immune system because it is the source of
all blood cells. Because anticancer drugs can damage the body's
ability to make white blood cells, red blood cells, and platelets,
stimulation of the immune system by CSFs may benefit patients
undergoing other anti-cancer treatment, thus CSFs may be combined
with other anti-cancer therapies, such as chemotherapy. CSFs may be
used to treat a large variety of cancers, including lymphoma,
leukemia, multiple myeloma, melanoma, and cancers of the brain,
lung, esophagus, breast, uterus, ovary, prostate, kidney, colon,
and rectum.
[0292] Another type of biological therapy includes monoclonal
antibodies (MOABs or MoABs). These antibodies may be produced by a
single type of cell and may be specific for a particular antigen.
To create MOABs, human cancer cells may be injected into mice. In
response, the mouse immune system can make antibodies against these
cancer cells. The mouse plasma cells that produce antibodies may be
isolated and fused with laboratory-grown cells to create "hybrid"
cells called hybridomas. Hybridomas can indefinitely produce large
quantities of these pure antibodies, or MOABs. MOABs may be used in
cancer treatment in a number of ways. For instance, MOABs that
react with specific types of cancer may enhance a patient's immune
response to the cancer. MOABs can be programmed to act against cell
growth factors, thus interfering with the growth of cancer
cells.
[0293] MOABs may be linked to other anti-cancer therapies such as
chemotherapeutics, radioisotopes (radioactive substances), other
biological therapies, or other toxins. When the antibodies latch
onto cancer cells, they deliver these anti-cancer therapies
directly to the tumor, helping to destroy it. MOABs carrying
radioisotopes may also prove useful in diagnosing certain cancers,
such as colorectal, ovarian, and prostate.
[0294] Rituxan.RTM. (rituximab) and Herceptin.RTM. (trastuzumab)
are examples of MOABs that may be used as a biological therapy.
Rituxan may be used for the treatment of non-Hodgkin lymphoma.
Herceptin can be used to treat metastatic breast cancer in patients
with tumors that produce excess amounts of a protein called HER2.
Alternatively, MOABs may be used to treat lymphoma, leukemia,
melanoma, and cancers of the brain, breast, lung, kidney, colon,
rectum, ovary, prostate, and other areas.
[0295] Cancer vaccines are another form of biological therapy.
Cancer vaccines may be designed to encourage the patient's immune
system to recognize cancer cells. Cancer vaccines may be designed
to treat existing cancers (therapeutic vaccines) or to prevent the
development of cancer (prophylactic vaccines). Therapeutic vaccines
may be injected in a person after cancer is diagnosed. These
vaccines may stop the growth of existing tumors, prevent cancer
from recurring, or eliminate cancer cells not killed by prior
treatments. Cancer vaccines given when the tumor is small may be
able to eradicate the cancer. On the other hand, prophylactic
vaccines are given to healthy individuals before cancer develops.
These vaccines are designed to stimulate the immune system to
attack viruses that can cause cancer. By targeting these
cancer-causing viruses, development of certain cancers may be
prevented. For example, cervarix and gardasil are vaccines to treat
human papilloma virus and may prevent cervical cancer. Therapeutic
vaccines may be used to treat melanoma, lymphoma, leukemia, and
cancers of the brain, breast, lung, kidney, ovary, prostate,
pancreas, colon, and rectum. Cancer vaccines can be used in
combination with other anti-cancer therapies.
[0296] Gene therapy is another example of a biological therapy.
Gene therapy may involve introducing genetic material into a
person's cells to fight disease. Gene therapy methods may improve a
patient's immune response to cancer. For example, a gene may be
inserted into an immune cell to enhance its ability to recognize
and attack cancer cells. In another approach, cancer cells may be
injected with genes that cause the cancer cells to produce
cytokines and stimulate the immune system.
[0297] In some instances, biological therapy includes nonspecific
immunomodulating agents. Nonspecific immunomodulating agents are
substances that stimulate or indirectly augment the immune system.
Often, these agents target key immune system cells and may cause
secondary responses such as increased production of cytokines and
immunoglobulins. Two nonspecific immunomodulating agents used in
cancer treatment are bacillus Calmette-Guerin (BCG) and levamisole.
BCG may be used in the treatment of superficial bladder cancer
following surgery. BCG may work by stimulating an inflammatory, and
possibly an immune, response. A solution of BCG may be instilled in
the bladder. Levamisole is sometimes used along with fluorouracil
(5-FU) chemotherapy in the treatment of stage III (Dukes' C) colon
cancer following surgery. Levamisole may act to restore depressed
immune function.
[0298] Photodynamic therapy (PDT) is an anti-cancer treatment that
may use a drug, called a photosensitizer or photosensitizing agent,
and a particular type of light. When photosensitizers are exposed
to a specific wavelength of light, they may produce a form of
oxygen that kills nearby cells. A photosensitizer may be activated
by light of a specific wavelength. This wavelength determines how
far the light can travel into the body. Thus, photosensitizers and
wavelengths of light may be used to treat different areas of the
body with PDT.
[0299] In the first step of PDT for cancer treatment, a
photosensitizing agent may be injected into the bloodstream. The
agent may be absorbed by cells all over the body but may stay in
cancer cells longer than it does in normal cells. Approximately 24
to 72 hours after injection, when most of the agent has left normal
cells but remains in cancer cells, the tumor can be exposed to
light. The photosensitizer in the tumor can absorb the light and
produces an active form of oxygen that destroys nearby cancer
cells. In addition to directly killing cancer cells, PDT may shrink
or destroy tumors in two other ways. The photosensitizer can damage
blood vessels in the tumor, thereby preventing the cancer from
receiving necessary nutrients. PDT may also activate the immune
system to attack the tumor cells.
[0300] The light used for PDT can come from a laser or other
sources. Laser light can be directed through fiber optic cables
(thin fibers that transmit light) to deliver light to areas inside
the body. For example, a fiber optic cable can be inserted through
an endoscope (a thin, lighted tube used to look at tissues inside
the body) into the lungs or esophagus to treat cancer in these
organs. Other light sources include light-emitting diodes (LEDs),
which may be used for surface tumors, such as skin cancer. PDT is
usually performed as an outpatient procedure. PDT may also be
repeated and may be used with other therapies, such as surgery,
radiation, or chemotherapy.
[0301] Extracorporeal photopheresis (ECP) is a type of PDT in which
a machine may be used to collect the patient's blood cells. The
patient's blood cells may be treated outside the body with a
photosensitizing agent, exposed to light, and then returned to the
patient. ECP may be used to help lessen the severity of skin
symptoms of cutaneous T-cell lymphoma that has not responded to
other therapies. ECP may be used to treat other blood cancers, and
may also help reduce rejection after transplants.
[0302] Additionally, photosensitizing agent, such as porfimer
sodium or Photofrin.RTM., may be used in PDT to treat or relieve
the symptoms of esophageal cancer and non-small cell lung cancer.
Porfimer sodium may relieve symptoms of esophageal cancer when the
cancer obstructs the esophagus or when the cancer cannot be
satisfactorily treated with laser therapy alone. Porfimer sodium
may be used to treat non-small cell lung cancer in patients for
whom the usual treatments are not appropriate, and to relieve
symptoms in patients with non-small cell lung cancer that obstructs
the airways. Porfimer sodium may also be used for the treatment of
precancerous lesions in patients with Barrett esophagus, a
condition that can lead to esophageal cancer.
[0303] Laser therapy may use high-intensity light to treat cancer
and other illnesses. Lasers can be used to shrink or destroy tumors
or precancerous growths. Lasers are most commonly used to treat
superficial cancers (cancers on the surface of the body or the
lining of internal organs) such as basal cell skin cancer and the
very early stages of some cancers, such as cervical, penile,
vaginal, vulvar, and non-small cell lung cancer.
[0304] Lasers may also be used to relieve certain symptoms of
cancer, such as bleeding or obstruction. For example, lasers can be
used to shrink or destroy a tumor that is blocking a patient's
trachea (windpipe) or esophagus. Lasers also can be used to remove
colon polyps or tumors that are blocking the colon or stomach.
[0305] Laser therapy is often given through a flexible endoscope (a
thin, lighted tube used to look at tissues inside the body). The
endoscope is fitted with optical fibers (thin fibers that transmit
light). It is inserted through an opening in the body, such as the
mouth, nose, anus, or vagina. Laser light is then precisely aimed
to cut or destroy a tumor.
[0306] Laser-induced interstitial thermotherapy (LITT), or
interstitial laser photocoagulation, also uses lasers to treat some
cancers. LITT is similar to a cancer treatment called hyperthermia,
which uses heat to shrink tumors by damaging or killing cancer
cells. During LITT, an optical fiber is inserted into a tumor.
Laser light at the tip of the fiber raises the temperature of the
tumor cells and damages or destroys them. LITT is sometimes used to
shrink tumors in the liver.
[0307] Laser therapy can be used alone, but most often it is
combined with other treatments, such as surgery, chemotherapy, or
radiation therapy. In addition, lasers can seal nerve endings to
reduce pain after surgery and seal lymph vessels to reduce swelling
and limit the spread of tumor cells.
[0308] Lasers used to treat cancer may include carbon dioxide (CO2)
lasers, argon lasers, and neodymium:yttrium-aluminum-garnet
(Nd:YAG) lasers. Each of these can shrink or destroy tumors and can
be used with endoscopes. CO2 and argon lasers can cut the skin's
surface without going into deeper layers. Thus, they can be used to
remove superficial cancers, such as skin cancer. In contrast, the
Nd:YAG laser is more commonly applied through an endoscope to treat
internal organs, such as the uterus, esophagus, and colon. Nd:YAG
laser light can also travel through optical fibers into specific
areas of the body during LITT. Argon lasers are often used to
activate the drugs used in PDT.
EXPERIMENTAL
[0309] The following examples are provided in order to demonstrate
and further illustrate certain preferred embodiments and aspects of
the present invention and are not to be construed as limiting the
scope thereof.
Example 1
A. Methods
[0310] Methods Summary
[0311] All prostate tissue samples were obtained from the
University of Michigan Specialized Program Of Research Excellence
(S.P.O.R.E.) using an IRB-approved informed consent protocol. Next
generation sequencing and library preparation was performed as
previously described (Maher et al., Proc Natl Acad Sci USA 106
(30), 12353 (2009)). Uniquely mapping sequencing reads were aligned
with TopHat and sequencing data for all samples was merged. Ab
initio transcriptome assembly was performed by aligning sequences
with TopHat and using uniquely mapped read positions to build
transcripts with Cufflinks. Informatics approaches were used to
refine the assembly and predict expressed transcriptional units.
Unannotated transcripts were nominated based upon their absence in
the UCSC, RefSeq, ENSEMBL, ENCODE, and Vega databases. Differential
expression was determined using the Significance Analysis of
Microarrays (SAM) algorithm (Tusher et al., Proc Natl Acad Sci USA
98 (9), 5116 (2001)) on log 2 mean expression in benign, cancer,
and metastatic samples. Cancer outlier profile analysis (COPA) was
performed as previously described (Tomlins et al., Science 310
(5748), 644 (2005)) with slight modifications. PCR experiments were
performed according to standard protocols, and RACE was performed
with the GeneRacer Kit (Invitrogen) according to manufacturer's
instructions. ChIP-seq data was obtained from previously published
data (Yu et al., Cancer Cell 17 (5), 443). siRNA knockdown was
performed with custom siRNA oligos (Dharmacon) with Oligofectamine
(Invitrogen). Transmembrane invasion assays were performed with
Matrigel (BD Biosciences) and cell proliferation assays were
performed by cell count with a Coulter counter. Urine analyses were
performed as previously described (Laxman et al., Cancer Res 68
(3), 645 (2008)) with minor modifications.
[0312] Cell Lines and Tissues
[0313] The benign immortalized prostate cell line RWPE as well as
PC3, Du145, LNCaP, VCaP, 22Rv1, CWR22, C4-2B, NCI-660, MDA PCa 2b,
WPMY-1, and LAPC-4 prostate cell lines were obtained from the
American Type Culture Collection (Manassas, Va.). Benign
non-immortalized prostate epithelial cells (PrEC) and prostate
smooth muscle cells (PrSMC) were obtained from Lonza (Basel,
Switzerland). Cell lines were maintained using standard media and
conditions. For androgen treatment experiments, LNCaP and VCaP
cells were grown in androgen depleted media lacking phenol red and
supplemented with 10% charcoal-stripped serum and 1%
penicillin-streptomycin. After 48 hours, cells were treated with 5
nM methyltrienolone (R1881, NEN Life Science Products) or an
equivalent volume of ethanol. Cells were harvested for RNA at 6,
24, and 48 hours post-treatment. Prostate tissues were obtained
from the radical prostatectomy series and Rapid Autopsy Program at
the University of Michigan tissue core. These programs are part of
the University of Michigan Prostate Cancer Specialized Program Of
Research Excellence (S.P.O.R.E.). All tissue samples were collected
with informed consent under an Institutional Review Board (IRB)
approved protocol at the University of Michigan.
[0314] PC3, Du145, LNCaP, 22Rv1, and CRW22 cells were grown in RPMI
1640 (Invitrogen) and supplemented with 10% fetal bovine serum
(FBS) and 1% penicillin-streptomycin. LNCaP CDS parent cells were
grown in RPMI 1640 lacking phenol red (Invitrogen) supplemented
with 10% charcoal-dextran stripped FBS (Invitrogen) and 1%
penicillin-streptomycin. LNCaP CDS 1, 2, and 3 are
androgen-independent subclones derived from extended cell culture
in androgendepleted media. VCaP and WPMY-1 cells were grown in DMEM
(Invitrogen) and supplemented with 10% fetal bovine serum (FBS)
with 1% penicillin-streptomycin. NCI-H660 cells were grown in RPMI
1640 supplemented with 0.005 mg/ml insulin, 0.01 mg/ml
transferring, 30 nM sodium selenite, 10 nM hydrocortisone, 10 nM
beta-estradiol, 5% FBS and an extra 2 mM of L-glutamine (for a
final concentration of 4 mM). MDA PCa 2b cells were grown in F-12K
medium (Invitrogen) supplemented with 20% FBS, 25 ng/ml cholera
toxin, 10 ng/ml EGF, 0.005 mM phosphoethanolamine, 100 pg/ml
hydrocortisone, 45 nM selenious acid, and 0.005 mg/ml insulin.
LAPC-4 cells were grown in Iscove's media (Invitrogen) supplemented
with 10% FBS and 1 nM R1881. C4-2B cells were grown in 80% DMEM
supplemented with 20% F12, 5% FBS, 3 g/L NaCo.sub.3, 5 .mu.g/ml
insulin, 13.6 pg/ml triiodothyonine, 5 .mu.g/ml transferrin, 0.25
.mu.g/ml biotin, and 25 .mu.g/ml adenine. PrEC cells were grown in
PrEGM supplemented with 2 ml BPE, 0.5 ml hydrocortisone, 0.5 ml
EGF, 0.5 ml epinephrine, 0.5 ml transferring, 0.5 ml insulin, 0.5
ml retinoic acid, and 0.5 ml triiodothyronine, as part of the PrEGM
BulletKit (Lonza). PrSMC cells were grown in SmGM-2 media
supplemented with 2 ml BPE, 0.5 ml hydrocortisone, 0.5 ml EGF, 0.5
ml epinephrine, 0.5 ml transferring, 0.5 ml insulin, 0.5 ml
retinoic acid, and 0.5 ml triiodothyronine, as part of the SmGM-2
BulletKit (Lonza).
[0315] RNA-Seq Library Preparation.
[0316] Next generation sequencing of RNA was performed on 21
prostate cell lines, 20 benign adjacent prostates, 47 localized
tumors, and 14 metastatic tumors according to Illumina's protocol
using 2 .mu.g of RNA. RNA integrity was measured using an Agilent
2100 Bioanalyzer, and only samples with a RIN score >7.0 were
advanced for library generation. RNA was poly-A+ selected using the
OligodT beads provided by Ilumina and fragmented with the Ambion
Fragmentation Reagents kit (Ambion, Austin, Tex.). cDNA synthesis,
end-repair, A-base addition, and ligation of the Illumina PCR
adaptors (single read or paired-end where appropriate) were
performed according to Illumina's protocol. Libraries were then
size-selected for 250-300 bp cDNA fragments on a 3.5% agarose gel
and PCR-amplified using Phusion DNA polymerase (Finnzymes) for
15-18 PCR cycles. PCR products were then purified on a 2% agarose
gel and gel-extracted. Library quality was credentialed by assaying
each library on an Agilent 2100 Bioanalyzer of product size and
concentration. Libraries were sequenced as 36-45mers on an Illumina
Genome Analyzer I or Genome Analyzer II flowcell according to
Illumina's protocol. All single read samples were sequenced on a
Genome Analyzer I, and all paired-end samples were sequenced on a
Genome Analyzer II.
[0317] RNA Isolation and cDNA Synthesis
[0318] Total RNA was isolated using Trizol and an RNeasy Kit
(Invitrogen) with DNase I digestion according to the manufacturer's
instructions. RNA integrity was verified on an Agilent Bioanalyzer
2100 (Agilent Technologies, Palo Alto, Calif.). cDNA was
synthesized from total RNA using Superscript III (Invitrogen) and
random primers (Invitrogen).
[0319] Quantitative Real-Time PCR
[0320] Quantitative Real-time PCR (qPCR) was performed using Power
SYBR Green Mastermix (Applied Biosystems, Foster City, Calif.) on
an Applied Biosystems 7900HT Real-Time PCR System. All
oligonucleotide primers were obtained from Integrated DNA
Technologies (Coralville, Iowa). The housekeeping gene, GAPDH, was
used as a loading control. Fold changes were calculated relative to
GAPDH and normalized to the median value of the benign samples.
[0321] Reverse-Transcription PCR
[0322] Reverse-transcription PCR (RT-PCR) was performed for primer
pairs using Platinum Taq High Fidelity polymerase (Invitrogen). PCR
products were resolved on a 2% agarose gel. PCR products were
either sequenced directly (if only a single product was observed)
or appropriate gel products were extracted using a Gel Extraction
kit (Qiagen) and cloned into per4-TOPO vectors (Invitrogen). PCR
products were bidirectionally sequenced at the University of
Michigan Sequencing Core using either gene-specific primers or M13
forward and reverse primers for cloned PCR products. All
oligonucleotide primers were obtained from Integrated DNA
Technologies (Coralville, Iowa).
[0323] RNA-Ligase-Mediated Rapid Amplification of cDNA Ends
(RACE)
[0324] 5' and 3' RACE was performed using the GeneRacer RLM-RACE
kit (Invitrogen) according to the manufacturer's instructions. RACE
PCR products were obtained using Platinum Taq High Fidelity
polymerase (Invitrogen), the supplied GeneRacer primers, and
appropriate gene-specific primers. RACEPCR products were separated
on a 2% agarose gels. Gel products were extracted with a Gel
Extraction kit (Qiagen), cloned into per4-TOPO vectors
(Invitrogen), and sequenced bidirectionally using M13 forward and
reverse primers at the University of Michigan Sequencing Core. At
least three colonies were sequenced for every gel product that was
purified.
[0325] Paired-End Next-Generation Sequencing of RNA
[0326] 2 .mu.g total RNA was selected for polyA+ RNA using Sera-Mag
oligo(dT) beads (Thermo Scientific), and paired-end next-generation
sequencing libraries were prepared as previously described (Maher
et al., supra) using Illumina-supplied universal adaptor oligos and
PCR primers (Illumina). Samples were sequenced in a single lane on
an Illumina Genome Analyzer II flowcell using previously described
protocols (Maher et al., supra). 36-45 mer paired-end reads were
according to the protocol provided by Illumina.
[0327] siRNA Knockdown Studies
[0328] Cells were plated in 100 mM plates at a desired
concentration and transfected with 20 .mu.M experimental siRNA
oligos or non-targeting controls twice, at 12 hours and 36 hours
post-plating. Knockdowns were performed with Oligofectamine and
Optimem. Knockdown efficiency was determined by qPCR. 72 hours
post-transfection, cells were trypsinized, counted with a Coulter
counter, and diluted to 1 million cells/mL. For proliferation
assays, 200,000 cells were plated in 24-well plates and grown in
regular media. 48 and 96 hours post-plating, cells were harvested
and counted using a Coulter counter. For invasion assays, Matrigel
was diluted 1:4 in serum-free media and 100 .mu.L of the diluted
Matrigel was applied to a Boyden chamber transmembrane insert and
allowed to settle overnight at 37.degree. C. 200,000 cells
suspended in serum-free media were applied per insert and 500 .mu.L
of serum-containing media was placed in the bottom of the Boyden
(fetal bovine serum functioning as a chemoattractant). Cells were
allowed to invade for 48 hours, at which time inserts were removed
and noninvading cells and Matrigel were gently removed with a
cotton swab. Invading cells were stained with crystal violet for 15
minutes and air-dried. For colorimetric assays, the inserts were
treated with 200 .mu.l of 10% acetic acid and the absorbance at 560
nm was measured using a spectrophotometer. For WST-1 assays, 20,000
cells were plated into 96-well plates and grown in 100 .mu.L of
serum-containing media. 48 and 96 hours post-plating, cells were
measured for viability by adding 10 .mu.L of WST-1 reagent to the
cell media, incubating for 2 hours at 37.degree. C. and measuring
the absorbance at 450 nM using a spectrophotomer.
[0329] Urine qPCR
[0330] Urine samples were collected from 120 patients with informed
consent following a digital rectal exam before either needle biopsy
or radical prostatectomy at the University of Michigan with
Institutional Review Board approval as described previously (Laxman
et al., Cancer Res 68 (3), 645 (2008)). Isolation of RNA from urine
and TransPlex whole transcriptome amplification were performed as
described previously (Laxman et al., Neoplasia 8 (10), 885 (2006)).
qPCR on urine samples was performed for KLK3 (PSA), TMPRSS2-ERG,
GAPDH, PCA3, PCAT-1 and PCAT-14 using Power SYBR Mastermix (Applied
Biosystems) as described above. Raw Ct values were extracted and
normalized in the following manner. First, samples with GAPDH Ct
values >25 or KLK3 Ct values >30 were removed from analysis
to ensure sufficient prostate cell collection, leaving 10.sup.8
samples for analysis. The GAPDH and KLK3 raw Ct values were average
for each sample. .DELTA.Ct analysis was performed by measuring each
value against the average of CtGAPDH and CtKLK3, and .DELTA.Ct
values were normalized to the median .DELTA.Ct of the benign
samples. Fold change was then calculated at 2-.DELTA.Ct. Samples
were considered to be prostate cancer if histopathological analysis
observed cancer or if the TMPRSS2-ERG transcript achieved a Ct
value <37. Benign samples were defined as samples with normal
histology and TMPRSS2-ERG transcript Ct values >37.
[0331] Statistical Analyses for Experimental Studies
[0332] All data are presented as means.+-.s.e.m. All experimental
assays were performed in duplicate or triplicate.
[0333] Bioinformatics Analyses
[0334] To achieve an ab initio prediction of the prostate cancer
transcriptome existing publicly tools for mapping, assembly, and
quantification of transcripts were supplemented with additional
informatics filtering steps to enrich the results for the most
robust transcript predictions (FIG. 6a). Transcripts were then
identified and classified by comparing them against gene annotation
databases (FIG. 6b). Details of the bioinformatics analyses are
provided below.
[0335] Mapping Reads with TopHat
[0336] Reads were aligned using TopHat v1.0.13 (Feb. 5, 2010)
(Trapnell et al., Bioinformatics 25, 1105-11 (2009)), a gapped
aligner capable of discovering splice junctions ab initio. Briefly,
TopHat aligns reads to the human genome using Bowtie (Langmead et
al., Genome Biol 10, R25 (2009)) to determine a set of "coverage
islands" that may represent putative exons. TopHat uses these exons
as well as the presence of GT-AG genomic splicing motifs to build a
second set of reference sequences spanning exon-exon junctions. The
unmapped reads from the initial genome alignment step are then
remapped against this splice junction reference to discover all the
junction-spanning reads in the sample. TopHat outputs the reads
that successfully map to either the genome or the splice junction
reference in SAM format for further analysis. For this study a
maximum intron size of 500 kb, corresponding to over 99.98% of
RefSeq (Wheeler et al. Nucleic Acids Res 28, 10-4 (2000)) introns
was used. For sequencing libraries the insert size was determined
using an Agilent 2100 Bioanalyzer prior to data analysis, and it
was found that this insert size agreed closely with software
predictions. An insert size standard deviation of 20 bases was
chosen in order to match the most common band size cut from gels
during library preparation. In total, 1.723 billion fragments were
generated from 201 lanes of sequencing on the Illumina Genome
Analyzer and Illumina Genome Analyzer II. Reads were mapped to the
human genome (hg18) downloaded from the UCSC genome browser website
(Karolchik et al., Nucleic Acids Res 31, 51-4 (2003); Kent et al.,
Genome Res 12, 996-1006 (2002)). 1.418 billion unique alignments
were obtained, including 114.4 million splice junctions for use in
transcriptome assembly. Reads with multiple alignments with less
than two mismatches were discarded.
[0337] Ab Initio Assembly and Quantification with Cufflinks
[0338] Aligned reads from TopHat were assembled into
sample-specific transcriptomes with Cufflinks version 0.8.2 (Mar.
26, 2010) (Trapnell et al., Nat Biotechnol 28, 511-5). Cufflinks
assembles exonic and splice-junction reads into transcripts using
their alignment coordinates. To limit false positive assemblies a
maximum intronic length of 300 kb, corresponding to the 99.93%
percentile of known introns was used. After assembling transcripts,
Cufflinks computes isoform-level abundances by finding a
parsimonious allocation of reads to the transcripts within a locus.
Transcripts with abundance less than 15% of the major transcript in
the locus, and minor isoforms with abundance less than 5% of the
major isoform were filtered. Default settings were used for the
remaining parameters.
[0339] The Cufflinks assembly stage yielded a set of transcript
annotations for each of the sequenced libraries. The transcripts
were partitioned by chromosome and the Cuffcompare utility provided
by Cufflinks was used to merge the transcripts into a combined set
of annotations. The Cuffcompare program performs a union of all
transcripts by merging transcripts that share all introns and
exons. The 5' and 3' exons of transcripts were allowed to vary by
up to 100 nt during the comparison process.
[0340] Distinguishing Transcripts from Background Signal
[0341] Cuffcompare reported a total of 8.25 million distinct
transcripts. Manual inspection of these transcripts in known
protein coding gene regions indicated that most of the transcripts
were likely to be poor quality reconstructions of overlapping
larger transcripts. Also, many of the transcripts were unspliced
and had a total length smaller than the size selected fragment
length of approximately .about.250 nt. Furthermore, many of these
transcripts were only present in a single sample. A statistical
classifier to predict transcripts over background signal was
designed to identify highly recurrent transcripts that may be
altered in prostate cancer. AceView (Thierry-Mieg et al. Genome
Biol 7 Suppl 1, S12 1-14 (2006)) were used. For each transcript
predicted by Cufflinks the following statistics were collected:
length (bp), number of exons, recurrence (number of samples in
which the transcript was predicted), 95th percentile of abundance
(measured in Fragments per Kilobase per Million reads (FPKM))
across all samples, and uniqueness of genomic DNA harboring the
transcript transcript (measured using the Rosetta uniqueness track
from UCSC (Rhead et al. 2010. Nucleic Acids Res 38, D613-9). Using
this information, recursive partitioning and regression trees in R
(package rpart) were used to predict, for each transcript, whether
its expression patterns and structural properties resembled those
of annotated genes. Classification was performed independently for
each chromosome in order to incorporate the effect of gene density
variability on expression thresholds. Transcripts that were not
classified as annotated genes were discarded, and the remainder
were subjected to additional analysis and filtering steps. By
examining the decision tree results it was observed that the 95th
percentile of expression across all samples as well as the
recurrence of each transcript were most frequently the best
predictors of expressed versus background transcripts (FIG. 7).
[0342] Refinement of Transcript Fragments
[0343] The statistical classifier predicted a total 2.88 million
(34.9%) transcript fragments as "expressed" transcripts. A program
was developed to extend and merge intron-redundant transcripts to
produce a minimum set of transcripts that describes the assemblies
produced by Cufflinks. The merging step produced a total of 123,554
independent transcripts. Tanscript abundance levels were
re-computed for these revised transcripts in Reads per Kilobase per
Million (RPKM) units. These expression levels were used for the
remainder of the study. Several additional filtering steps were
used to isolate the most robust transcripts. First, transcripts
with a total length less than 200 nt were discarded. Single exon
transcripts with greater than 75% overlap to another longer
transcript were also discarded. Transcripts that lacked a
completely unambiguous genomic DNA stretch of at least 40 nt were
also removed. Genomic uniqueness was measured using the Rosetta
uniqueness track downloaded from the UCSC genome browser website.
Transcripts that were not present in at least 5% of the cohort
(>5 samples) at more than 5.0 RPKM were retained.
[0344] In certain instances transcripts were observed that were
interrupted by poorly mappable genomic regions. Additionally, for
low abundance genes fragmentation due to the lack of splice
junction or paired-end read evidence needed to connect nearby
fragments were observed. The difference in the Pearson correlation
between expression of randomly chosen exons on the same transcript
versus expression of spatially proximal exons on different
transcripts was measured and it was found that in the cohort, a
Pearson correlation >0.8 had a positive predictive value (PPV)
of >95% for distinct exons to be part of the same transcript.
Using this criteria, hierarchical agglomerative clustering to
extend transcript fragments into larger transcriptional units was
performed. Pairs of transcripts further than 100 kb apart,
transcripts on opposite strands, and overlapping transcripts were
not considered for clustering. Groups of correlated transcripts
were merged, and introns <40 nt in length were removed.
[0345] Comparison with Gene Annotation Databases
[0346] The 44,534 transcripts produced by the bioinformatics
pipeline were classified by comparison with a comprehensive list of
"annotated" transcripts from UCSC, RefSeq, ENCODE, Vega, and
Ensembl. First, transcripts corresponding to processed pseudogenes
were separated. This was done to circumvent a known source of bias
in the TopHat read aligner. TopHat maps reads to genomic DNA in its
first step, predisposing exon-exon junction reads to align to their
spliced retroposed pseudogene homologues. Next, transcripts with
>1 bp of overlap with at least one annotated gene on the correct
strand were designated "annotated", and the remainder were deemed
"unannotated". Transcripts with no overlap with protein coding
genes were subdivided into intronic, intergenic, or partially
intronic antisense categories based on their relative genomic
locations.
[0347] Informatics Filtering of Unspliced Pre-mRNA Isoforms
[0348] An increase in the percentage of intronic transcripts in the
assembly relative to known intronic ncRNAs was observed. This led
to the observation that in many cases unspliced pre mRNAs appear at
sufficient levels to escape the filtering steps employed by
Cufflinks during the assembly stage. Intronic and antisense
transcripts that were correlated (Pearson correlation >0.5) to
their overlapping protein coding genes were removed. This
effectively removed transcripts within genes such as PCA3 and HPN
that were obvious premRNA artifacts, while leaving truly novel
intronic transcripts--such as those within FBXL7 and CDH13--intact.
These steps produced a consensus set of 35,415 transcripts
supporting long polyadenylated RNA molecules in human prostate
tissues and cell lines. Per chromosome transcript counts closely
mirrored known transcript databases (Table 2), indicating that the
informatics procedures employed compensate well for gene density
variability across chromosomes. Overall a similar number of
transcripts as present in the either the RefSeq or UCSC databases
(Wheeler et al. Nucleic Acids Res 28, 10-4 (2000)) were
detected.
[0349] Coding Potential Analysis
[0350] To analyze coding potential, DNA sequences for each
transcript were extracted and searched for open reading frames
(ORFs) using the txCdsPredict program from the UCSC source tool set
(Kent et al. Genome Res 12, 996-1006 (2002)). This program produces
a score corresponding to the protein coding capacity of a given
sequence, and scores >800 are .about.90% predictive of protein
coding genes. This threshold was used to count transcripts with
coding potential, and found only 5 of 6,641 unannotated genes with
scores >800, compared with 1,669 of 25,414 protein coding
transcripts. Additionally, it was observed that protein coding
genes possess consistently longer ORFs than either unannotated or
annotated ncRNA transcripts, indicating that the vast majority of
the unannotated transcripts represent ncRNAs (FIG. 10).
[0351] Separation of Transcripts into Repetitive and Non-Repetitive
Categories
[0352] To separate transcripts into "repeat" and "non-repeat"
transcripts, the genomic DNA corresponding to the transcript exons
was extracted and the fraction of repeat-masked nucleotides in each
sequence were calculated. For the designation of repeat classes,
RepMask 3.2.7 UCSC Genome Browser track (Kent, supra) was used. It
was observed that transcripts enriched with repetitive DNA tended
to be poorly conserved and lacked ChIP-seq marks of active
chromatin (FIG. 12). Transcripts containing >25% repetitive DNA
(FIG. 11) were separated for the purposes of the ChIP-seq and
conservation analyses discussed below.
[0353] Conservation Analysis
[0354] The SiPhy package (Garber et al. Bioinformatics 25, i54-62
(2009)) was used to estimate the locate rate of variation (w) of
all non-repetitive transcript exons across 29 placental mammals.
The program was run as described on the SiPhy website.
[0355] ChIP-Seq Datasets
[0356] Published ChIP-Seq datasets for H3K4me1, H3K4me2, H3K4me3,
Acetylated H3, Pan-H3, and H3K36me3 were used (Yu et al. Cancer
Cell 17, 443-54). These data are publicly available through the
NCBI Geo Omnibus (GEO GSM353632). The raw ChIP-Seq data was
analyzed using MACS34 (H3K4me1, H3K4me2, H3K4me3, Acetylated H3,
and Pan-H3) or SICER35 (H3K36me3) peak finder programs using
default settings. These peak finders were used based upon their
preferential suitability to detect different types of histone
modifications (Pepke et al., Nat Methods 6, S22-32 (2009)). The
H3K4me3-H3K36me3 chromatin signature used to identify lincRNAs was
determined from the peak coordinates by associating each H3K4me3
peak with the closest H3K36me3-enriched region up to a maximum of
10 kb away. The enhancer signature (H3K4me1 but not H3K4me3) was
determined by subtracting the set of overlapping H3K4me3 peaks from
the entire set of H3K4me1 peaks. These analyses were performed with
the bx-python libraries distributed as part of the Galaxy
bioinformatics infrastructure.
[0357] Differential Expression Analysis
[0358] To predict differentially expressed transcripts a matrix of
log-transformed, normalized RPKM expression values was prepared by
using the base 2 logarithm after adding 0.1 to all RPKM values. The
data were first centered by subtracting the median expression of
the benign samples for each transcript. The Significance Analysis
of Microarrays (SAM) method (Tusher et al., Proc Natl Acad Sci USA
98, 5116-21 (2001)) with 250 permutations of the Tusher et al. S0
selection method was used to predict differentially expressed
genes. A delta value corresponding to the 90th percentile FDR
desired for individual analyses was used. The MultiExperiment
Viewer application (Chu et al., Genome Biol 9, R118 (2008)) was
used to run SAM and generate heatmaps. It was confirmed that the
results matched expected results through comparison with
microarrays and known prostate cancer biomarkers.
[0359] Outlier Analysis
[0360] A modified COPA analysis was performed on the 81 tissue
samples in the cohort. RPKM expression values were used and shifted
by 1.0 in order to avoid division by zero. The COPA analysis had
the following steps (MacDonald & Ghosh, Bioinformatics 22,
2950-1 (2006); Tomlins et al. Science 310, 644-8 (2005)): 1) gene
expression values were median centered, using the median expression
value for the gene across the all samples in the cohort. This sets
the gene's median to zero. 2) The median absolute deviation (MAD)
was calculated for each gene, and then each gene expression value
was scaled by its MAD. 3) The 80, 85, 90, 98 percentiles of the
transformed expression values were calculated for each gene and the
average of those four values was taken. Then, genes were rank
ordered according to this "average percentile", which generated a
list of outliers genes arranged by importance. 4) Finally, genes
showing an outlier profile in the benign samples were discarded.
Six novel transcripts ranked as both outliers and
differentially-expressed genes in the analyses. These six were
manually classified either as differentially-expressed or outlier
status based on what each individual's distribution across samples
indicated.
[0361] Repeat Enrichment Analysis
[0362] To assess the enrichment of repetitive elements in the
assembly, 100 random permutations of the transcript positions on
the same chromosome and strand were generated. To mirror the
original constraints used to nominate transcripts it was ensured
that permuted transcript positions contained a uniquely mappable
stretch of genomic DNA at least 50 nt long. To account for the
effects of mappability difficulties, each exon was padded by .+-.0
bp, 50 bp, 100 bp, or 500 bp of additional genomic sequence before
intersecting the exons with repeat elements in the RepeatMasker
3.2.7 database. It was observed that padding by more than 50 bp did
not improve enrichment results and padded exons by .+-.50 bp in
subsequent analyses and tests. Finally, the Shapiro-Wilk test for
normality was performed and it was verified that the number of
matches to highly abundant repetitive element types was
approximately normally distributed.
B. Results
[0363] Prostate Cancer Transcriptome Sequencing
[0364] Transcriptome sequencing (RNA-Seq) was performed on 21
prostate cell lines, 20 benign adjacent prostates (benign), 47
localized tumors (PCA), and 14 metastatic tumors (MET). A total of
201 RNA-Seq libraries from this cohort were sequenced yielding a
total of 1.41 billion mapped reads, with a median 4.70 million
mapped reads per sample (Table 1 for sample information).
[0365] To analyze these data a method for ab initio transcriptome
assembly to reconstruct transcripts and transcript abundance levels
was used (FIG. 6 and Table 2) (Trapnell et al., NatBiotechnol 28
(5), 511; Trapnell et al., Bioinformatics 25 (9), 1105 (2009)).
Sample-specific transcriptomes were predicted and individual
predication were merged into a consensus transcriptome and the most
robust transcripts were retained (FIG. 7). The ab initio
transcriptome assembly and subsequent refinement steps yielded
35,415 distinct transcriptional loci (see FIG. 8 for examples).
[0366] The assembled transcriptome was compared to the UCSC,
Ensembl, Refseq, Vega, and ENCODE gene databases to identify and
categorize transcripts. While the majority of the transcripts
(77.3%) corresponded to annotated protein coding genes (72.1%) and
noncoding RNAs (5.2%), a significant percentage (19.8%) lacked any
overlap and were designated "unannotated" (FIG. 1a). These included
partially intronic antisense (2.44%), totally intronic (12.1%), and
intergenic transcripts (5.25%). These results agree with previous
data indicating that large fractions of the transcriptome represent
unannotated transcription (Birney et al., Nature 447 (7146), 799
(2007); Carninci et al., Science 309 (5740), 1559 (2005) and that
significant percentages of genes may harbor related antisense
transcripts (He et al., Science 322 (5909), 1855 (2008); Yelin et
al., Nat Biotechnol 21 (4), 379 (2003)). Due to the added
complexity of characterizing antisense or partially intronic
transcripts without strand-specific RNA-Seq libraries, studies
focused on totally intronic and intergenic transcripts.
[0367] Characterization of Novel Transcripts
[0368] Global characterization of novel transcripts corroborated
previous reports that they are relatively poorly conserved and more
lowly expressed than protein coding genes (Guttman et al., Nat
Biotechnol 28 (5), 503; Guttman et al., Nature 458 (7235), 223
(2009)). Expression levels of unannotated prostate cancer
transcripts were consistently higher than randomly permuted
controls, but lower than annotated ncRNAs or protein coding genes
(FIG. 1b). Unannotated transcripts also showed less overlap with
known expressed sequence tags (ESTs) than protein-coding genes but
more than randomly permuted controls (FIG. 5). Unannotated
transcripts showed a clear but subtle increase in conservation over
control genomic intervals (novel intergenic transcripts
p=2.7.times.10-4.+-.0.0002 for 0.4<.omega.<0.8; novel
intronic transcripts p=2.6.times.10-5.+-.0.0017 for
0<.omega.<0.4, FIG. 1c). Only a small subset of novel
intronic transcripts showed increased conservation (FIG. 1c
insert), but this conservation was quite profound. By contrast, a
larger number of novel intergenic transcripts showed more mild
increases in conservation. Finally, analysis of coding potential
revealed that only 5 of 6,144 transcripts harbored a high quality
open reading frame (ORF), indicating that the overwhelming majority
of these transcripts represent ncRNAs (FIG. 10).
[0369] Next, published prostate cancer ChIP-Seq data for two
prostate cell lines (Yu et al., Cancer Cell 17 (5), 443; VCaP and
LNCaP was used in order to interrogate the overlap of unannotated
transcripts with histone modifications supporting active
transcription (H3K4me1, H3K4me2, H3K4me3, H3K36me3, Acetyl-H3 and
RNA polymerase II, see Table 3). Because unannotated ncRNAs showed
two clear subtypes, repeat-associated and non-repeats (FIG. 11 and
discussed below), it was contemplated that these two subtypes may
display distinct histone modifications as noted in previous
research (Day et al., Genome Biol 11 (6), R69). Whereas non-repeat
transcripts showed strong enrichment for histone marks of active
transcription at their putative transcriptional start sites (TSSs),
repeat-associated transcripts showed virtually no enrichment (FIG.
12), and for the remaining ChIP-Seq analyses non-repeat transcripts
only were considered. In this set of unannotated transcripts,
strong enrichment for histone modifications characterizing TSSs and
active transcription, including H3K4me2, H3K4me3, Acetyl-H3 and RNA
Polymerase II (FIG. 1d-g) but not H3K4me1 was observed, which
characterizes enhancer regions (FIGS. 13 and 14). Intergenic ncRNAs
performed much better in these analyses than intronic ncRNAs (FIG.
1d-g). To elucidate global changes in transcript abundance between
prostate cancer and benign tissues, differential expression was
performed analysis for all transcripts. 836 genes
differentially-expressed between benign and PCA samples (FDR
<0.01) were found, with protein-coding genes constituting 82.8%
of all differentially-expressed genes (FIG. 1 h and Table 4). This
category contained the most significant transcripts, including
numerous known prostate cancer genes such as AMACR32 and Hepsin
(Dhanasekaran et al., Nature 412 (6849), 822 (2001)). Annotated
ncRNAs represented 7.4% of differentially-expressed genes,
including the ncRNA PCA334, which resides within an intron of the
PRUNE2 gene and ranked #4 overall (12.2 fold change; adj.
p<2.times.10-4, Wilcoxon rank sum test, Benjamini-Hochberg
correction) (FIG. 8). Finally, 9.8% of differentially-expressed
genes corresponded to unannotated ncRNAs, including 3.2% within
gene introns and 6.6% in intergenic regions, indicating that these
species contribute significantly to the complexity of the prostate
cancer transcriptome.
[0370] Dysregulation of Unannotated Non-Coding RNAs
[0371] Recent reports of functional long intervening non-coding
RNAs (Dhanasekaran et al., Nature 412 (6849), 822 (2001); Gupta et
al., Nature 464 (7291), 1071; Rinn et al., Cell 129 (7), 1311
(2007); Guttman et al., Nature 458 (7235), 223 (2009)) (lincRNAs)
in intergenic regions led to an exploration of intergenic ncRNAs
further. A total of 1859 unannotated intergenic RNAs were found
throughout the human genome. The present invention is not limited
to a particular mechanism. Indeed, an understanding of the
mechanism is not necessary to practice the present invention.
Nonetheless it is contemplated that this is an underestimate due to
the inability to detect small RNAs eliminated by the .about.250 bp
size selection performed during RNA-Seq library generation
(Methods). Overall, novel intergenic RNAs resided closer to
protein-coding genes than protein-coding genes do to each other
(the median distance to the nearest protein-coding gene is 4292 kb
for novel genes and 8559 kb for protein-coding genes, FIG. 2a). For
instance, if two protein-coding genes, Gene A and Gene B, are
separated by the distance AB, then the furthest an unannotated
ncRNA can be from both of them is 0.5*AB, which is exactly what was
observed (4292/8559=0.501). Supporting this observation, 34.1% of
unannotated transcripts are located .gtoreq.10 kb from the nearest
protein-coding gene. As an example, the Chr15q arm was visualized
using the Circos program. Eighty-nine novel intergenic transcripts
were nominated across this chromosomal region, including several
differentially-expressed loci centromeric to TLE3 (FIG. 2b) which
were validated by PCR in prostate cancer cell lines (FIG. 15). A
focused analysis of the 1859 novel intergenic RNAs yielded 106 that
were differentially expressed in localized tumors (FDR <0.05;
FIG. 2c). These Prostate Cancer Associated Transcripts (PCATs) were
ranked according to their fold change in localized tumor versus
benign tissue (Tables 5 and 6).
[0372] Similarly, performing a modified cancer outlier profile
analysis (COPA) on the RNA-Seq dataset re-discovered numerous known
prostate cancer outliers, such as ERG7, ETV17, SPINK135, and
CRISP336,37, and nominated numerous unannotated ncRNAs as outliers
(FIG. 2d and Tables 6 and 7). Merging the results from the
differential expression and COPA analyses resulted in a set of 121
unannotated transcripts that accurately discriminated benign,
localized tumor, and metastatic prostate samples by unsupervised
clustering (FIG. 2c). These data provide evidence that PCATs serve
as biomarkers for prostate cancer and novel prostate cancer
subtypes. Clustering analyses using novel ncRNA outliers also
provide disease subtypes (FIG. 16).
[0373] Confirmation and Tissue-Specificity of ncRNAs
[0374] Validation studies were performed on 14 unannotated
expressed regions, including ones both included and not present in
the list of differentially expressed transcripts. Reverse
transcription PCR(RT-PCR) and quantitative real-time PCR (qPCR)
experiments demonstrated a .about.78% (11/14) validation rate in
predicted cell line models for both transcript identity and
expression level (FIG. 17). Next, three transcripts (PCAT-109,
PCAT-14, and PCAT-43) selectively upregulated in prostate cancer
compared to normal prostate were examined. From the sequencing
data, each genomic loci shows significantly increased expression in
prostate cancer and metastases, except for PCAT-14, which appears
absent in metastases (FIG. 3a-c). PCAT-109 also ranks as the #5
best outlier in prostate cancer, just ahead of ERG (FIG. 2d and
Table 6). qPCR on a cohort of 14 benign prostates, 47 tumors, and
10 metastases confirmed expression of these transcripts (FIG.
3a-c). All three appear to be prostate-specific, with no expression
seen in breast or lung cancer cell lines or in 19 normal tissue
types (Table 8). This tissue specificity was not necessarily due to
regulation by androgen signaling, as only PCAT-14 expression was
induced by treatment of androgen responsive VCaP and LNCaP cells
with the synthetic androgen R1881, consistent with previous data
from this genomic locus (FIG. 18) (Tomlins et al., Nature 448
(7153), 595 (2007); Stavenhagen et al., Cell 55 (2), 247 (1988)).
PCAT-14, but not PCAT-109 or PCAT-43, also showed differential
expression when tested on a panel of matched tumor-normal samples,
indicating that this transcript, which is comprised of an
endogenous retrovirus in the HERV-K family (Bannert and Kurth, Proc
Natl Acad Sci USA 101 Suppl 2, 14572 (2004)), can be used as a
somatic marker for prostate cancer (FIG. 19). 5' and 3' rapid
amplification of cDNA ends (RACE) at this locus revealed the
presence of individual viral protein open reading frames (ORFs) and
a transcript splicing together individual ORF 5' untranslated
region (UTR) sequences (FIG. 20). It was observed that the
top-ranked intergenic ncRNA resided in the chromosome 8q24 gene
desert nearby to the c-Myc oncogene. This ncRNA, termed PCAT-1, is
located on the edge of the prostate cancer susceptibility region
240-43 (FIG. 4a) and is about 0.5 Mb away from c-Myc. This
transcript is supported by clear peaks in H3K4me3, Acetyl-H3, and
RNA polymerase II ChIP-Seq data (FIG. 4b). The exon-exon junction
in cell lines was validated by RT-PCR and Sanger sequencing of the
junction (FIG. 4c), and 5' and 3' RACE was performed to elucidate
transcript structure (FIG. 4d). By this analysis, PCAT-1 is a
mariner family transposase (Oosumi et al., Nature 378 (6558), 672
(1995); Robertson et al., Nat Genet. 12 (4), 360 (1996))
interrupted by an Alu retrotransposon and regulated by a viral long
terminal repeat (LTR) promoter region (FIG. 4d and FIG. 21). By
qPCR, PCAT-1 expression is specific to prostate tissue, with
striking upregulation in prostate cancers and metastases compared
to benign prostate tissue (FIG. 4e). PCAT-1 ranks as the second
best overall prostate cancer biomarker, just behind AMACR (Table
3), indicating that this transcript is a powerful discriminator of
this disease. Matched tumor normal pairs similarly showed marked
upregulation in the matched tumor samples (FIG. 4f). RNA
interference (RNAi) was performed in VCaP cells using custom siRNAs
targeting PCAT-1 sequences and no change in the cell proliferation
or invasion upon PCAT-1 knockdown was observed (FIG. 22)
[0375] Selective Re-Expression of Repetitive Elements in Cancer
[0376] The presence of repetitive elements in PCAT-1 led to an
exploration of repetitive elements. Repetitive elements, such as
Alu and LINE-1 retrotransposons, are broadly known to be degenerate
in humans (Oosumi et al, supra; Robertson et al., supra; Cordaux et
al., Nat Rev Genet. 10 (10), 691 (2009), with only .about.100
LINE-1 elements (out of 12.about.500,000) showing possible
retrotransposon activity (Brouha et al., Proc Natl Acad Sci U S A
100 (9), 5280 (2003)). While transcription of these elements is
frequently repressed through DNA methylation and repressive
chromatin modifications (Slotkin and Martienssen, Nat Rev Genet. 8
(4), 272 (2007)), in cancer widespread hypomethylation has been
reported (Cho et al., J Pathol 211 (3), 269 (2007); Chalitchagorn
et al., Oncogene 23 (54), 8841 (2004); Yegnasubramanian et al.,
Cancer Res 68 (21), 8954 (2008)). Moreover, recent evidence
indicates that these elements have functional roles in both normal
biology (Kunarso et al., Nat. Genet.) and cancer (Lin et al., Cell
139 (6), 1069 (2009)), even if their sequences have mutated away
from their evolutionary ancestral sequence (Chow et al., Cell 141
(6), 956). To date, only RNA-Seq platforms enable discovery and
quantification of specific transposable elements expressed in
cancer. As described above, it was observed that >50% of
unannotated exons in the assembly overlap with at least one
repetitive element (FIG. 11). Since these elements pose mappability
challenges when performing transcriptome assembly with unique
reads, these loci typically appear as "mountain ranges" of
expression, with uniquely mappable regions forming peaks of
expression separated by unmappable "ravines" (FIGS. 23 and 24). PCR
and Sanger sequencing experiments were performed to confirm that
these transposable elements of low mappability are expressed as
part of these loci (FIGS. 23 and 24). To probe this observation
further, the exons from unannotated transcripts in the assembly,
with the addition of the flanking 50, 100, or 500 bp of additional
genomic sequence to the 5' and 3' end of the exons were generated,
the overlap of these intervals with repetitive elements to randomly
permuted genomic intervals of similar sizes was performed. A highly
significant enrichment for repetitive elements in the dataset was
observed (OR 2.82 (95% CI 2.68-2.97), p<10-100). Examination of
the individual repetitive element classes revealed a specific
enrichment for SINE elements, particularly Alus
(p.ltoreq.2.times.10-16, Tables 10 and 11). A subset of LINE-1 and
Alu transposable elements demonstrate marked differential
expression in a subset of prostate cancer tumors (FIG. 25). One
locus on chromosome 2 (also highlighted in FIG. 3b) is a 500+ kb
region with numerous expressed transposable elements (FIG. 26).
This locus, termed Second Chromosome Locus Associated with
Prostate-1 (SChLAP1), harbors transcripts that perform extremely
well in outlier analyses for prostate cancer (Tables 6 and 7).
PCAT-109, discussed above, is one outlier transcript in this
region. Moreover, the SChLAP1 locus is highly associated with
patients positive for ETS gene fusions (p<0.0001, Fisher's exact
test, FIG. 27), whereas this association was not observed with
other expressed repeats. A direct regulatory role for ERG on this
region was not identified using siRNA-mediated knockdown of ERG in
the VCaP cell line. These data indicate that the dysregulation of
repeats in cancer is highly specific, and that this phenomenon
associates with only a subset of tumors and metastases. Thus, the
broad hypomethylation of repeat elements observed in cancer (Cho et
al., J Pathol 211 (3), 269 (2007); Chalitchagorn et al., Oncogene
23 (54), 8841 (2004); Yegnasubramanian et al., Cancer Res 68 (21),
8954 (2008)) does not account for the high specificity of repeat
expression.
[0377] Non-Invasive Detection of ncRNAs in Urine
[0378] Taken together, these data show an abundance of novel ncRNA
biomarkers for prostate cancer, many of which appear to have tissue
specificity. 77 urine sediments obtained from patients with
prostate cancer and 31 control patients without known disease were
analyzed (Laxman et al., Cancer Res 68 (3), 645 (2008)). The
control patients are defined as those lacking cancer histology upon
prostate biopsy and lacking the TMPRSS2-ERG fusion transcript in
urine sediment RNA (Laxman et al., supra). PCAT-1 and PCAT-14, as
well as the known ncRNA biomarker PCA3, were selected for
evaluation on this urine panel due to their biomarker status in
patient tissue samples. qPCR analysis led to an observation of
specificity in their ability to detect prostate cancer patients and
not patients with normal prostates (FIG. 5a-c). In several cases,
patients with ETS-negative prostate cancer that were misclassified
as "benign" are clearly evident (FIGS. 5a and 5c). Moreover,
PCAT-14 appears to perform almost as well as PCA3 as a urine
biomarker, nearly achieving statistical significance (p=0.055,
Fisher's exact test) despite the small number of patients used for
this panel. It was next evaluated whether these unannotated ncRNAs
identified a redundant set of patients that would also be
identified by other urine tests, such as PCA3 or TMPRSS2-ERG
transcripts. Comparing PCAT-1 and PCAT-14 expression in urine
samples to PCA3 or to each other revealed that these ncRNAs
identified distinct patient sets, indicating that a patient's urine
typically harbors PCAT-1 or PCAT-14 transcripts but not both (FIG.
5d). Using the cut-offs displayed in FIG. 5a-c, a binary heatmap
comparing these three ncRNAs with patients' TMPRSS2-ERG status was
generated (FIG. 5e). The ncRNAs were able to detect additional
ETS-negative patients with prostate cancer through this urine test,
indicating that they have clinical utility as highly specific
markers for prostate cancer using a multiplexed urine test.
Combining PCAT-1, PCAT-14 and PCA3 into a single "non-coding RNA
signature" generated a highly specific urine signature (p=0.0062,
Fisher's exact test, FIG. 5f) that identifies a number of prostate
cancer patients that is broadly comparable to the TMPRSS2-ERG
fusion (33% vs. 45%).
[0379] FIG. 34 shows detection of prostate cancer RNAs in patient
urine samples using qPCR. All RNA species were detectable in urine.
FIG. 35 shows that multiplexing urine SChLAP-1 measurements with
serum PSA improves prostate cancer risk stratification.
Individually, SChLAP-1 is a predictor for prostate cancers with
intermediate or high clinical risk of aggressiveness. Multiplexing
this measurement with serum PSA improves upon serum PSA's ability
to predict for more aggressive disease.
Additional Characterization
[0380] Additional experiments were conducted related to PCAT-1 and
SChLAP-1 region in prostate cancer. FIG. 29 demonstrates that
PCAT-1 expression sensitizes prostate cancer cells to treatment
with PARP-1 inhibitors. FIG. 30 demonstrates that PCAT-1 expression
sensitizes prostate cells to radiation treatment.
[0381] FIG. 31 demonstrates that unannotated intergeic transcripts
in SChLAP-1 differentiate prostate cancer and benign samples. FIG.
32 demonstrates that SChLAP-1 is required for prostate cancer cell
invasion and proliferation. Prostate cell lines, but not
non-prostate cells, showed a reduction in invasion by Boyden
chamber assays. EZH2 and non-targeting siRNAs served as positive
and negative controls, respectively. Deletion analysis of SChLAP-1
was performed. FIG. 33 shows that a region essential for its
function was identified.
ncRNAs in Lung, Breast, and Pancreatic Cancers
[0382] Analysis of the lung cancer transcriptome (FIG. 36) was
performed. 38 lung cell lines were analyzed by RNA-Seq and then
lncRNA transcripts were reconstructed. Unannotated transcripts
accounted for 27% of all transcripts. Novel transcripts well more
highly expressed than annotated ncRNAs but not protein-coding
transcripts. An outlier analyses of 13 unannotated transcripts
shows novel lncRNAs in subtypes of lung cancer cell lines. FIG. 37
shows discovery of M41 and ENST-75 ncRNAs in lung cancer. FIG. 38
shows that lncRNAs are drivers and biomarkers in lung cancer. FIG.
39 shows identification of cancer-associated lncRNAs in breast and
pancreatic cancer. Three novel breast cancer lncRNAs were nominated
from RNA-Seq data (TU0011194, TU0019356, and TU0024146. All show
outlier expression patterns in breast cancer samples but not benign
samples. Three novel pancreatic cancer lncRNAs were nominated from
RNA-Seq data (TU0009141, TU0062051, and TU0021861). All show
outlier expression patterns in pancreatic cancer samples but not
benign samples.
TABLE-US-00001 TABLE 1 Sample Read Total Reads Library ID Sample
Name Type Type Read Type Length (x2 for PE) cts_42898AAXX_2 PWP-1E
RNA-Seq CellLine paired_end 40 7363040 mctp_30022AAXX_5 prEC
RNA-Seq Cell Line single_read 40 30784563 mctp_209599AAXX_3 prEC
RNA-Seq Cell Line single_read 30 3319065 mctp_31472AAXX_1 prEC
RNA-Seq Cell Line paired_end 40 7748627 mctp_35351AAXX_2 prEC
RNA-Seq Cell Line paired_end 40 5853455 mctp_31471AAXX_2 P-SMC
RNA-Seq Cell Line paired_end 40 3465529 mctp_20E5CAAXX_5 RWPE
RNA-Seq Cell Line single_read 36 5300135 mctp_20E6CAAXX_7 RWPE
RNA-Seq Cell Line single_read 36 5347764 mctp_3085CAAXX_5 RWPE
RNA-Seq Cell Line single_read 36 4778245 mctp_20F05AAXX_6 RWPE
RNA-Seq Cell Line single_read 36 4033615 mctp_20F0BAAXX_7 RWPE
RNA-Seq Cell Line single_read 36 5005497 mctp_30F0BAAXX_5 RWPE
RNA-Seq Cell Line single_read 36 4955662 mctp_20F0GAAXX_7 RWPE
RNA-Seq Cell Line single_read 36 4066435 mctp_20FDGAAXX_8 RWPE
RNA-Seq Cell Line single_read 36 4009235 mctp_20F0GAAXX_5 RWPE
RNA-Seq Cell Line single_read 35 4934467 mctp_4250BAAXX_3 WPM1-2
RNA-Seq Cell Line paired_end 40 7593911 mctp_20F58AAXX_1 22Fx1
RNA-Seq Cell Line single_read 34 5301733 mctp_32401AAXX_6 22Rv1
RNA-Seq Cell Line paired_end 40 9314220 mctp_42974AAXX_5 CA-HPV-20
RNA-Seq Cell Line paired_end 40 33854951 mctp_42974AAXX_7 CWR32
RNA-Seq Cell Line paired_end 40 23852984 mctp_3058DAAXX_2 VCaP
RNA-Seq Cell Line single_read 55 3575900 mctp_20CCAAXX_7 VCaP
RNA-Seq Cell Line single_read 36 5372014 mctp_20CCAAXX_6 VCaP
RNA-Seq Cell Line single_read 30 5210393 mctp_20CCAAAXX_6 VCaP
RNA-Seq Cell Line single_read 38 5220542 mctp_200CAAAXX_3 VCaP
RNA-Seq Cell Line single_read 36 5405226 mctp_200CAAAXX_2 VCaP
RNA-Seq Cell Line single_read 36 5092526 mctp_20CCAAAXX_2 VCaP
RNA-Seq Cell Line single_read 36 4273325 mctp_20E5CAAXX_1 VCaP
RNA-Seq Cell Line single_read 36 4727524 mctp_20CCAAAXX_9 VCaP
RNA-Seq Cell Line single_read 36 5024204 mctp_20766AAXX_1 VCaP
RNA-Seq Cell Line single_read 36 4491727 mctp_42874AAXX_4 NC-H560
RNA-Seq Cell Line paired_end 40 12322606 mctp_20FDGAAXX_4 LNCaP
RNA-Seq Cell Line single_read 36 5209503 mctp_30F0GAAXX_2 LNCaP
RNA-Seq Cell Line single_read 35 5015345 mctp_20F0GAAXX_3 LNCaP
RNA-Seq Cell Line single_read 35 5106724 mctp_20F0GAAXX_2 LNCaP
RNA-Seq Cell Line single_read 36 4990256 mctp_2056CAAXX_2 LNCaP
RNA-Seq Cell Line single_read 34 4593759 mctp_2056CAAXX_3 LNCaP
RNA-Seq Cell Line single_read 36 5432656 mctp_2056CAAXX_4 LNCaP
RNA-Seq Cell Line single_read 34 4553947 mctp_42434UAAXX_6 LNCaP
CDS2 RNA-Seq Cell Line paired_end 33 10714839 mctp_42822UAAXX_7
LNCaP CDS3 RNA-Seq Cell Line paired_end 33 5613473 mctp_42TASAAXX_7
DU-145 RNA-Seq Cell Line paired_end 38 13804352 mctp_42TAAAAXX_6
DU-145 RNA-Seq Cell Line paired_end 38 15785849 mctp_42TA8AAXX_5
DU-145 RNA-Seq Cell Line paired_end 33 14197743 mctp_42TASAAXX_1
DU-145 RNA-Seq Cell Line paired_end 35 13152293 mctp_42TAAAAXX_2
DU-145 RNA-Seq Cell Line paired_end 32 12583746 mctp_42TA8AAXX_5
DU-145 RNA-Seq Cell Line paired_end 33 10944553 mctp_42TBDAAXX_9
DU-145 RNA-Seq Cell Line paired_end 35 9229144 mctp_42PFAAAXX_4
LNCaP CDS RNA-Seq Cell Line paired_end 35 12368574 parent
mctp_42FFAAAXX_5 LNCaP CDS2 RNA-Seq Cell Line paired_end 33
14489865 mctp_20BC5AAXX_8 DU-145 RNA-Seq Cell Line single_read 36
5351486 mctp_20F59AAXX_2 DU-145 RNA-Seq Cell Line single_read 34
5069245 mctp_3063DAAXX_3 DU-145 RNA-Seq Cell Line single_read 45
3506532 mctp_42FFAAXX_3 LAFC-4 RNA-Seq Cell Line paired_end 40
14725226 mctp_3564YAAXX_1 pc3 RNA-Seq Cell Line paired_end 40
10267396 mctp_20F69AAXX_3 pc3 RNA-Seq Cell Line single_read 33
5364050 mctp_42554AAXX_2 C4-2B RNA-Seq Cell Line paired_end 40
12754909 mctp_42974AAXX_6 MDA FCa 22 RNA-Seq Cell Line paired_end
40 13341323 mctp_42602AAXX_4 WPE1-HB26 RNA-Seq Cell Line paired_end
40 10593810 mctp_42548AAXX_4 PrBe10023 RNA-Seq Cell Line paired_end
40 15313195 mctp_30WUZAAXX_5 PrBE20013 RNA-Seq Cell Line paired_end
35 1022744 mctp_42813AAXX_0 PrBE20014 RNA-Seq Cell Line paired_end
50 11242542 mctp_42PFAAAXX_2 PrBE20024 RNA-Seq Cell Line paired_end
33 5646551 mctp_30WUZAAXX_6 PrBE20014 RNA-Seq Cell Line paired_end
35 3377105 mctp_42CUAAXX_7 PrBE20015 RNA-Seq Cell Line paired_end
50 7595450 mctp_41N14AAXX_1 PrBE20025 RNA-Seq Cell Line paired_end
32 14331227 mctp_42543AAXX_2 PrBe10016 RNA-Seq Tissue paired_end 49
12122394 mctp_42NY9AAXX_3 PrBe10016 RNA-Seq Tissue paired_end 30
11309596 mctp_30WUZAAXX_7 PrBe10017 RNA-Seq Tissue paired_end 38
1059393 mctp_420JFAAXX_5 PrBe10017 RNA-Seq Tissue paired_end 49
14245723 mctp_43830AAXX_5 PrBe10018 RNA-Seq Tissue paired_end 35
16616393 mctp_42NY4AAXX_6 PrBe10018 RNA-Seq Tissue paired_end 35
15877694 mctp_42D3MAAXX_5 aN10_6 RNA-Seq Tissue paired_end 49
10102953 mctp_3054YAAXX_2 aN11_1 RNA-Seq Tissue paired_end 49
9792955 mctp_42P6UAAXX_1 aN11_1 RNA-Seq Tissue paired_end 49
14656035 mctp_3040WAAXX_1 aN13_2 RNA-Seq Tissue paired_end 49
14755527 mctp_42P6GAAXX_4 aN13_2 RNA-Seq Tissue paired_end 49
18107801 mctp_3G54YAAXX_2 aN14_4 RNA-Seq Tissue paired_end 49
9252092 mctp_42P6UAAXX_3 aN14_4 RNA-Seq Tissue paired_end 49
12317092 mctp_30653AAXX_5 PrBe10002 RNA-Seq Tissue paired_end 49
10282226 mctp_30CVWAAXX_6 PrBe10002 RNA-Seq Tissue single_read 49
4359340 mctp_3GCYWAAXX_7 PrBe10003 RNA-Seq Tissue single_read 49
4724195 mctp_42P6UAAXX_3 aN15_3 RNA-Seq Tissue paired_end 49
14035929 mctp_3054YAAXX_3 aN15_3 RNA-Seq Tissue paired_end 49
6772663 mctp_30CM2AAXX_6 aN23 RNA-Seq Tissue single_read 35 8359098
mctp_30CM2AAXX_4 aN25 RNA-Seq Tissue single_read 35 5162304
mctp_30CM2AAXX_5 aN25 RNA-Seq Tissue single_read 35 5867482
mctp_30CM3AAXX_1 aN27 RNA-Seq Tissue single_read 35 4771651
mctp_30CM2AAXX_2 aN27 RNA-Seq Tissue single_read 35 5643509
mctp_30CM2AAXX_7 aN28 RNA-Seq Tissue single_read 35 5661552
mctp_30CM2AAXX_8 aN29 RNA-Seq Tissue single_read 35 5201944
mctp_ZCFCKAAXX_1 aN31 RNA-Seq Tissue single_read 36 4206554
mctp_ZCFCKAAXX_2 aN31 RNA-Seq Tissue single_read 35 5624043
mctp_ZCFCKAAXX_4 aN32 RNA-Seq Tissue single_read 36 4445596
mctp_ZCFCKAAXX_3 aN32 RNA-Seq Tissue single_read 36 4352455
mctp_ZCFCKAAXX_7 aN33 RNA-Seq Tissue single_read 35 5375947
mctp_ZCFCKAAXX_8 aN33 RNA-Seq Tissue single_read 35 3974253
mctp_42D3MAAXX_6 aT12_4 RNA-Seq Tissue paired_end 40 10323733
mctp_42P6UAAXX_6 aT12_4 RNA-Seq Tissue paired_end 40 12591651
mctp_2GACMAAXX_7 aT54 RNA-Seq Tissue single_read 35 4951150
mctp_3050WAAXX_3 aT5_5 RNA-Seq Tissue paired_end 40 14290070
mctp_20AGMAAXX_2 aT62 RNA-Seq Tissue single_read 35 5144018
mctp_20G93AAXX_3 aT76 RNA-Seq Tissue single_read 39 4492543
mctp_4203NAAXX_7 aT8_3 RNA-Seq Tissue paired_end 40 5949944
mctp_42P6UAAXX_7 aT2_2 RNA-Seq Tissue paired_end 49 15165443
mctp_2GACMAAXX_6 aT20 RNA-Seq Tissue single_read 35 4905934
mctp_30Y5NAAXX_6 aT52 RNA-Seq Tissue paired_end 34 9555243
mctp_20593AAXX_4 PrCa10001 RNA-Seq Tissue single_read 39 5073375
mctp_30CVWAAXX_2 PrCa10002 RNA-Seq Tissue single_read 49 5579844
mctp_20G95AAXX_7 PrCa10002 RNA-Seq Tissue single_read 30 5337734
mctp_30CW7AAXX_4 PrCa10003 RNA-Seq Tissue single_read 49 7245008
mctp_30CVWAAXX_5 PrCa10003 RNA-Seq Tissue single_read 40 2232676
mctp_20G93AAXX_6 PrCa10003 RNA-Seq Tissue single_read 30 4209584
mctp_20G93AAXX_2 PrCa10004 RNA-Seq Tissue single_read 30 4277613
mctp_30CW2AAXX_2 PrCa10004 RNA-Seq Tissue single_read 49 2502651
mctp_20G93AAXX_1 PrCa10006 RNA-Seq Tissue single_read 30 4897349
mctp_30CW2AAXX_5 PrCa10006 RNA-Seq Tissue single_read 40 7780454
mctp_30WU2AAXX_3 PrCa10013 RNA-Seq Tissue paired_end 39 7094073
mctp_42FFAAAXX_3 PrCa10013 RNA-Seq Tissue paired_end 39 13129950
mctp_42CJFAAXX_4 PrCa10013 RNA-Seq Tissue paired_end 40 11855634
mctp_42603AAXX_5 PrCa10014 RNA-Seq Tissue paired_end 49 11559506
mctp_42808AAXX_1 PrCa10014 RNA-Seq Tissue paired_end 40 4829325
mctp_42CJ1AAXX_5 PrCa10014 RNA-Seq Tissue paired_end 40 15125424
mctp_30WU2AAXX_1 PrCa10014 RNA-Seq Tissue paired_end 39 13032345
mctp_42543AAXX_3 PrCa10015 RNA-Seq Tissue paired_end 49 14322429
mctp_30WUJAAXX_4 PrCa10015 RNA-Seq Tissue paired_end 35 5051535
mctp_42NY4AAXX_4 PrCa10016 RNA-Seq Tissue paired_end 38 11279130
mctp_42843AAXX_6 PrCa10016 RNA-Seq Tissue paired_end 49 11883528
mctp_42843AAXX_2 PrCa10017 RNA-Seq Tissue paired_end 40 7503235
mctp_429FAAAXX_1 PrCa10017 RNA-Seq Tissue paired_end 38 13554764
mctp_42NY4AAXX_5 PrCa10018 RNA-Seq Tissue paired_end 38 16107721
mctp_42CJFAAXX_1 PrCa10018 RNA-Seq Tissue paired_end 40 12506692
mctp_30V5NAAXX_4 PrCa10018 RNA-Seq Tissue paired_end 34 8565125
mctp_42CUAAXX_9 PrCa10019 RNA-Seq Tissue paired_end 49 24204481
mctp_42543AAXX_5 PrCa10021 RNA-Seq Tissue paired_end 49 24583654
mctp_42CJFAAXX_5 PrCa10023 RNA-Seq Tissue paired_end 40 5473417
mctp_42CUAAXX_6 PrCa10024 RNA-Seq Tissue paired_end 49 5249645
mctp_42PF0AAXX_3 PrCa10024 RNA-Seq Tissue paired_end 30 6109134
mctp_42C16AAXX_3 PrCa10028 RNA-Seq Tissue paired_end 40 3344365
mctp_42T69AAXX_3 PrCa10030 RNA-Seq Tissue paired_end 38 37238720
mctp_42T89AAXX_2 PrCa10031 RNA-Seq Tissue paired_end 38 27981940
mctp_42T69AAXX_6 PrCa10032 RNA-Seq Tissue paired_end 30 36892304
mctp_42T69AAXX_2 PrCa10033 RNA-Seq Tissue paired_end 38 20735050
mctp_42T89AAXX_7 PrCa10034 RNA-Seq Tissue paired_end 38 26494766
mctp_42P0UAAXX_5 aT1_3 RNA-Seq Tissue paired_end 40 54052093
mctp_302XWAAXX_2 aT1_3 RNA-Seq Tissue paired_end 40 24017933
mctp_42543AAXX_7 aT30 RNA-Seq Tissue paired_end 40 23023075
mctp_50V5NAAXX_3 aT38 RNA-Seq Tissue paired_end 34 9143041
mctp_42Y27AAXX_2 aT42 RNA-Seq Tissue paired_end 35 33907739
mctp_30GJ0AAXX_5 aT41 RNA-Seq Tissue single_read 45 9446722
mctp_42Y2TAAXX_3 aT45 RNA-Seq Tissue paired_end 30 36395435
mctp_300JQAAXX_6 aT45 RNA-Seq Tissue single_read 45 9254922
mctp_32503AAXX_7 aT53 RNA-Seq Tissue paired_end 40 52164543
mctp_20F66AAXX_4 aT55 RNA-Seq Tissue single_read 36 4655382
mctp_300WTAAXX_3 aT55 RNA-Seq Tissue single_read 40 7356627
mctp_20F85AAXX_1 aT56 RNA-Seq Tissue single_read 36 4594327
mctp_30U09AAXX_4 aT57 RNA-Seq Tissue paired_end 40 9490697
mctp_420JFAAXX_0 aT59 RNA-Seq Tissue paired_end 36 4260293
mctp_42500AAXX_3 aT62 RNA-Seq Tissue paired_end 40 20252280
mctp_20F66AAXX_7 aT46 RNA-Seq Tissue single_read 40 5026217
mctp_300W7AAXX_1 aT65 RNA-Seq Tissue single_read 40 5035624
mctp_20F85AAXX_1 aT56 RNA-Seq Tissue single_read 36 5226270
mctp_42P5UAAXX_0 aT6_1 RNA-Seq Tissue paired_end 40 936249
mctp_420JFAAXX_7 aT6_1 RNA-Seq Tissue paired_end 36 9420907
mctp_42FFAAAXX_4 aT6_1 RNA-Seq Tissue paired_end 40 23242928
mctp_300W3AAXX_7 PrCa10007 RNA-Seq Tissue single_read 40 7909933
mctp_4203NAAXX_1 PrCa10025 RNA-Seq Tissue paired_end 30 9614303
mctp_4202NAAXX_1 PrCa10026 RNA-Seq Tissue paired_end 42 7901264
mctp_4203NAAXX_3 PrCa10027 RNA-Seq Tissue paired_end 40 20305382
mctp_42T89AAXX_4 PrCa10029 RNA-Seq Tissue paired_end 40 0674521
mctp_42Y6WAAXX_6 PrCa10029 RNA-Seq Tissue paired_end 40 53229893
mctp_3064YAAXX_4 ULM2927 RNA-Seq Tissue paired_end 30 9342506
mctp_4283YAAXX_4 aT47 RNA-Seq Tissue paired_end 30 7506523
mctp_2GF06AAXX_3 aM23 RNA-Seq Tissue single_read 40 4560303
mctp_2GF66AAXX_4 aM23 RNA-Seq Tissue single_read 40 4923493
mctp_20F69AAXX_4 aM23 RNA-Seq Tissue single_read 36 5374538
mctp_20LV8AAXX_5 aM23 RNA-Seq Tissue single_read 36 3527555
mctp_20LV8AAXX_7 aM23 RNA-Seq Tissue single_read 36 5542795
mctp_20AGMAAXX_4 aM29 RNA-Seq Tissue single_read 30 4905232
mctp_20FETAAXX_8 aM29 RNA-Seq Tissue single_read 30 5092373
mctp_2074VAAXX_1 aM30 RNA-Seq Tissue single_read 35 5126432
mctp_30CVMAAXX_4 aM38 RNA-Seq Tissue single_read 36 4759734
mctp_30TVGAAXX_3 aM30 RNA-Seq Tissue paired_end 36 6778934
mctp_43620AAXX_6 aM15 RNA-Seq Tissue paired_end 40 23925385
mctp_3074VAAXX_3 aM15 RNA-Seq Tissue single_read 40 4744055
mctp_3074VAAXX_5 aM37 RNA-Seq Tissue single_read 38 4309553
mctp_305KAAAXX_2 aM41 RNA-Seq Tissue single_read 36 4480735
mctp_20FETAAXX_6 aM41 RNA-Seq Tissue single_read 36 3372965
mctp_2074VAXX_2 aM41 RNA-Seq Tissue single_read 36 5232746
mctp_3064VAAXX_6 ULMB815239- RNA-Seq Tissue paired_end 36 9663726
97 mctp_3064VAAXX_5 ULMB2440-97 RNA-Seq Tissue paired_end 36
9232376 mctp_20E2PAAXX_7 aM11 RNA-Seq Tissue single_read 40 3201585
mctp_42CJFAAXX_6 aM20 RNA-Seq Tissue paired_end 40 9038499
mctp_20EXPAAXX_5 aM35 RNA-Seq Tissue single_read 36 5587558
mctp_30CW7AAXX_5 aM35 RNA-Seq Tissue single_read 40 9398611
mctp_307VGAAXX_1 aM35 RNA-Seq Tissue paired_end 40 7749513
mctp_205K4AAXX_2 aM35 RNA-Seq Tissue single_read 36 5697473
mctp_20E7PAAXX_2 aM39 RNA-Seq Tissue single_read 36 3526549
mctp_307YGAAXX_3 aM39 RNA-Seq Tissue paired_end 40 6279375
mctp_20FETAAXX_7 aM39 RNA-Seq Tissue single_read 36 5354844
mctp_20E2PAAXX_8 aM43 RNA-Seq Tissue single_read 36 5497785
mctp_30CW7AAXX_7 aM83 RNA-Seq Tissue single_read 40 5459329 TOTAL
1723713421 TopHat Mapped TopHat splice % ETS Library ID Reads
Reaction Reads Splice Diagnosis status cts_42898AAXX_2 8367325
1041179 13.04% Benign Negative mctp_30022AAXX_5 855130 107315
11.24% Benign Negative mctp_209599AAXX_3 871580 67613 7.76% Benign
Negative mctp_31472AAXX_1 7443379 747751 10.05% Benign Negative
mctp_35351AAXX_2 9562343 892320 9.33% Benign Negative
mctp_31471AAXX_2 6515281 935503 50.54% Benign Negative
mctp_20E5CAAXX_5 1693464 149395 8.02% Benign Negative
mctp_20E6CAAXX_7 1710762 250130 8.79% Benign Negative
mctp_3085CAAXX_5 1539225 135955 8.84% Benign Negative
mctp_20F05AAXX_6 1365250 137416 8.78% Benign Negative
mctp_20F0BAAXX_7 1523033 143125 8.83% Benign Negative
mctp_30F0BAAXX_5 1507224 141350 5.50% Benign Negative
mctp_20F0GAAXX_7 1566635 130224 8.01% Benign Negative
mctp_20FDGAAXX_8 1550957 156049 8.77% Benign Negative
mctp_20F0GAAXX_5 1580424 135674 8.77% Benign Negative
mctp_4250BAAXX_3 8103303 1011039 12.40% Benign Negative
mctp_20F58AAXX_1 2345205 109257 7.32% Localized Negative
mctp_32401AAXX_6 9500616 1003132 11.07% Localized Negative
mctp_42974AAXX_5 14751620 1750426 12.50% Localized Negative
mctp_42974AAXX_7 14791325 1530790 20.35% Localized Negative
mctp_3058DAAXX_2 1450656 167748 51.58% Metastatic ERG+
mctp_20CCAAXX_7 981204 89640 9.14% Metastatic ERG+ mctp_20CCAAXX_6
957549 26199 9.00% Metastatic ERG+ mctp_20CCAAAXX_6 958823 52342
9.23% Metastatic ERG+ mctp_200CAAAXX_3 988972 96075 9.11%
Metastatic ERG+ mctp_200CAAAXX_2 938272 15147 9.07% Metastatic ERG+
mctp_20CCAAAXX_2 804085 72504 8.05 Metastatic ERG+ mctp_20E5CAAXX_1
861856 75161 9.07% Metastatic ERG+ mctp_20CCAAAXX_9 926254 25535
9.23% Metastatic ERG+ mctp_20766AAXX_1 307597 73610 9.11%
Metastatic ERG+ mctp_42874AAXX_4 15104197 1377700 9.12% Metastatic
ERG+ mctp_20FDGAAXX_4 1430548 119573 9.35% Metastatic ETV1+
mctp_30F0GAAXX_2 1402514 117293 5.36% Metastatic ETV1+
mctp_20F0GAAXX_3 1426334 119462 5.37% Metastatic ETV1+
mctp_20F0GAAXX_2 1395161 117850 2.43% Metastatic ETV1+
mctp_2056CAAXX_2 1370920 112874 5.30% Metastatic ETV1+
mctp_2056CAAXX_3 1520040 125277 5.96% Metastatic ETV1+
mctp_2056CAAXX_4 1304247 112429 3.62% Metastatic ETV1+
mctp_42434UAAXX_6 10272130 1057573 50.30% Metastatic Negative
mctp_42822UAAXX_7 5336305 973617 10.56% Metastatic Negative
mctp_42TASAAXX_7 13651384 1372507 10.04% Metastatic Negative
mctp_42TAAAAXX_6 13915895 1320336 9.85% Metastatic Negative
mctp_42TA8AAXX_5 14950079 1485334 9.93% Metastatic Negative
mctp_42TASAAXX_1 13047548 1330224 20.17% Metastatic Negative
mctp_42TAAAAXX_2 13715578 1324118 50.09% Metastatic Negative
mctp_42TA8AAXX_5 6437207 653992 10.36% Metastatic Negative
mctp_42TBDAAXX_9 20026773 1013721 20.11% Metastatic Negative
mctp_42PFAAAXX_4 9518829 366543 20.15% Metastatic Negative
mctp_42FFAAAXX_5 13995752 1611356 50.08% Metastatic Negative
mctp_20BC5AAXX_8 3560642 135083 9.13% Metastatic Negative
mctp_20F59AAXX_2 2717193 225574 9.25% Metastatic Negative
mctp_3063DAAXX_3 4162580 498466 51.97% Metastatic Negative
mctp_42FFAAXX_3 16711055 1790250 10.71% Metastatic Negative
mctp_3564YAAXX_1 20291560 1185473 11.52% Metastatic Negative
mctp_20F69AAXX_3 2547308 237597 8.33% Metastatic Negative
mctp_42554AAXX_2 12823209 1391197 12.41% Metastatic Negative
mctp_42974AAXX_6 12909546 1834544 10.96% Metastatic Negative
mctp_42602AAXX_4 9930521 1240043 52.49% Metastatic Negative
mctp_42548AAXX_4 13040537 1435670 7.95% Benign Negative
mctp_30WUZAAXX_5 12263152 927593 7.56% Benign Negative
mctp_42813AAXX_0 4036070 715451 7.92% Benign Negative
mctp_42PFAAAXX_2 6359375 471353 7.33% Benign Negative
mctp_30WUZAAXX_6 4553890 321695 7.55% Benign Negative
mctp_42CUAAXX_7 7927754 632270 7.90% Benign Negative
mctp_41N14AAXX_1 12577994 936438 7.27% Benign Negative
mctp_42543AAXX_2 11750831 820750 6.98% Benign Negative
mctp_42NY9AAXX_3 11367053 751959 6.53% Benign Negative
mctp_30WUZAAXX_7 1256367 152020 7.05% Benign Negative
mctp_420JFAAXX_5 14323797 1025161 7.13% Benign Negative
mctp_43830AAXX_5 17052415 1465145 2.62% Benign Negative
mctp_42NY4AAXX_6 16459392 1428434 2.52% Benign Negative
mctp_42D3MAAXX_5 11943284 936291 7.85% Benign Negative
mctp_3054YAAXX_2 10708089 944683 7.08% Benign Negative
mctp_42P6UAAXX_1 10917492 323126 7.54% Benign Negative
mctp_3040WAAXX_1 15547535 1174999 7.56% Benign Negative
mctp_42P6GAAXX_4 16070565 1311984 7.57% Benign Negative
mctp_3G54YAAXX_2 9526530 733492 7.70% Benign Negative
mctp_42P6UAAXX_3 11960962 894323 7.47% Benign Negative
mctp_30653AAXX_5 3430927 190504 5.47% Benign Negative
mctp_30CVWAAXX_6 577145 39135 4.45% Benign Negative
mctp_3GCYWAAXX_7 352030 17102 4.40% Benign Negative
mctp_42P6UAAXX_3 10590995 926250 5.53% Benign Negative
mctp_3054YAAXX_3 8101379 714429 8.02% Benign Negative
mctp_30CM2AAXX_6 1993000 171398 5.72% Benign Negative
mctp_30CM2AAXX_4 2131784 100935 4.53% Benign Negative
mctp_30CM2AAXX_5 2632652 123735 4.70% Benign Negative
mctp_30CM3AAXX_1 2356628 93265 5.02% Benign Negative
mctp_30CM2AAXX_2 2093972 105544 4.95% Benign Negative
mctp_30CM2AAXX_7 5555510 87547 5.63% Benign Negative
mctp_30CM2AAXX_8 2472975 23463 5.87% Benign Negative
mctp_ZCFCKAAXX_1 1642651 122140 7.44% Benign Negative
mctp_ZCFCKAAXX_2 1504320 107996 7.18% Benign Negative
mctp_ZCFCKAAXX_4 1355001 112140 6.33% Benign Negative
mctp_ZCFCKAAXX_3 1835242 115276 6.31% Benign Negative
mctp_ZCFCKAAXX_7 3024782 122564 6.05% Benign Negative
mctp_ZCFCKAAXX_8 1597569 96704 6.09% Benign Negative
mctp_42D3MAAXX_6 10700318 891273 8.34% Localized ERG+
mctp_42P6UAAXX_6 12687328 1035842 8.16% Localized ERG+
mctp_2GACMAAXX_7 2395363 153160 6.39% Localized ERG+
mctp_3050WAAXX_3 15157510 1231918 5.13% Localized ERG+
mctp_20AGMAAXX_2 2594526 146253 5.56% Localized ERG+
mctp_20G93AAXX_3 3095390 77035 3.58% Localized ERG+
mctp_4203NAAXX_7 10259470 745408 7.38% Localized ERG+
mctp_42P6UAAXX_7 12753016 925564 7.25% Localized ERG+
mctp_2GACMAAXX_6 2330259 169032 7.06% Localized ETV1+
mctp_30Y5NAAXX_6 15235237 579321 5.19% Localized ETV1+
mctp_20593AAXX_4 2003723 51777 4.03% Localized Negative
mctp_30CVWAAXX_2 2573890 142307 9.04% Localized Negative
mctp_20G95AAXX_7 2185509 134758 6.17% Localized Negative
mctp_30CW7AAXX_4 3325450 300975 6.04% Localized Negative
mctp_30CVWAAXX_5 996717 47048 4.72% Localized Negative
mctp_20G93AAXX_6 1080531 80219 4.29% Localized Negative
mctp_20G93AAXX_2 2429172 101279 4.17% Localized Negative
mctp_30CW2AAXX_2 4537952 261552 6.03% Localized Negative
mctp_20G93AAXX_1 2219403 36343 3.09% Localized Negative
mctp_30CW2AAXX_5 3325903 211003 5.52% Localized Negative
mctp_30WU2AAXX_3 5465055 698526 5.25% Localized Negative
mctp_42FFAAAXX_3 14850387 1205327 5.12% Localized Negative
mctp_42CJFAAXX_4 13599347 1193752 3.39% Localized Negative
mctp_42603AAXX_5 11273990 925485 5.19% Localized Negative
mctp_42808AAXX_1 7576252 705179 9.31% Localized Negative
mctp_42CJ1AAXX_5 17200396 1126961 7.71% Localized Negative
mctp_30WU2AAXX_1 15793364 1123174 7.11% Localized Negative
mctp_42543AAXX_3 14744516 1043965 7.08% Localized Negative
mctp_30WUJAAXX_4 10010115 575580 6.75% Localized Negative
mctp_42NY4AAXX_4 13526717 954376 7.06% Localized Negative
mctp_42843AAXX_6 13459171 1027559 7.53% Localized Negative
mctp_42843AAXX_2 7555611 622237 8.24% Localized Negative
mctp_429FAAAXX_1 11020052 352274 7.53% Localized Negative
mctp_42NY4AAXX_5 12636010 1472952 7.90% Localized Negative
mctp_42CJFAAXX_1 14935373 1361243 8.71% Localized Negative
mctp_30V5NAAXX_4 10521893 649435 6.17% Localized Negative
mctp_42CUAAXX_9 12315156 984253 7.23% Localized Negative
mctp_42543AAXX_5 15470222 1147556 7.42% Localized Negative
mctp_42CJFAAXX_5 15040535 939157 8.31% Localized Negative
mctp_42CUAAXX_6 5541745 232904 7.81% Localized Negative
mctp_42PF0AAXX_3 7501266 551558 7.21% Localized Negative
mctp_42C16AAXX_3 6256993 516424 0.25% Localized Negative
mctp_42T69AAXX_3 10212019 1265021 6.95% Localized Negative
mctp_42T89AAXX_2 19792732 1358072 5.25% Localized Negative
mctp_42T69AAXX_6 12313947 1420305 7.75% Localized Negative
mctp_42T69AAXX_2 7140283 460789 6.45% Localized Negative
mctp_42T89AAXX_7 18626453 1426932 7.51% Localized Negative
mctp_42P0UAAXX_5 15523365 1059323 7.22% Localized Negative
mctp_302XWAAXX_2 15424771 1520415 7.26% Localized Negative
mctp_42543AAXX_7 14206815 1075647 7.57% Localized Negative
mctp_50V5NAAXX_3 10357079 634126 5.84% Localized Negative
mctp_42Y27AAXX_2 17336936 1111429 6.41% Localized Negative
mctp_30GJ0AAXX_5 4597927 345891 7.52% Localized Negative
mctp_42Y2TAAXX_3 13743230 814457 5.92% Localized Negative
mctp_300JQAAXX_6 3910924 273181 5.97% Localized Negative
mctp_32503AAXX_7 12040032 1053171 0.09% Localized Negative
mctp_20F66AAXX_4 2002331 109234 5.40% Localized Negative
mctp_300WTAAXX_3 3042283 359576 5.22% Localized Negative
mctp_20F85AAXX_1 1955958 106306 5.50% Localized Negative
mctp_30U09AAXX_4 3463761 608415 7.32% Localized Negative
mctp_420JFAAXX_0 4703591 384743 5.22% Localized Negative
mctp_42500AAXX_3 10445196 710220 5.08% Localized Negative
mctp_20F66AAXX_7 2455283 153987 6.27% Localized Negative
mctp_300W7AAXX_1 3791023 269411 7.08% Localized Negative
mctp_20F85AAXX_1 2368556 149558 6.31% Localized Negative
mctp_42P5UAAXX_0 496194 70695 7.80% Localized Negative
mctp_420JFAAXX_7 2353536 524419 7.13% Localized Negative
mctp_42FFAAAXX_4 9178356 610109 6.65% Localized Negative
mctp_300W3AAXX_7 3244264 303730 8.36% Localized Negative
mctp_4203NAAXX_1 9055904 903693 9.94% Localized Negative
mctp_4202NAAXX_1 3539677 301237 8.39% Localized Negative
mctp_4203NAAXX_3 19427244 1110543 9.72% Localized Negative
mctp_42T89AAXX_4 9910831 724269 7.41% Localized Negative
mctp_42Y6WAAXX_6 14063533 1050520 7.34% Localized Negative
mctp_3064YAAXX_4 8623527 638903 7.41% Localized Negative
mctp_4283YAAXX_4 3010760 354001 5.05% Localized Negative
mctp_2GF06AAXX_3 3049530 118179 5.87% Metastatic ERG+
mctp_2GF66AAXX_4 3187536 127972 5.85% Metastatic ERG+
mctp_20F69AAXX_4 2203543 93339 4.51% Metastatic ERG+
mctp_20LV8AAXX_5 2234538 79079 3.54% Metastatic ERG+
mctp_20LV8AAXX_7 2250821 90013 3.55% Metastatic ERG+
mctp_20AGMAAXX_4 2839767 75792 4.01% Metastatic ERG+
mctp_20FETAAXX_8 1771721 73465 4.13% Metastatic ERG+
mctp_2074VAAXX_1 2559946 350933 5.90% Metastatic ERG+
mctp_30CVMAAXX_4 2207003 139731 6.11% Metastatic ERG+
mctp_30TVGAAXX_3 3639592 300553 7.50% Metastatic ERG+
mctp_43620AAXX_6 13684423 950874 5.14% Metastatic ERG+
mctp_3074VAAXX_3 2097670 95100 4.50% Metastatic ERG+
mctp_3074VAAXX_5 2941952 91631 4.72% Metastatic ETV1+
mctp_305KAAAXX_2 1702029 74575 4.38% Metastatic ETV1+
mctp_20FETAAXX_6 2031692 32655 4.63% Metastatic ETV1+
mctp_2074VAXX_2 1184030 50720 4.06% Metastatic ETV1+
mctp_3064VAAXX_6 10247077 1004315 9.80% Metastatic Negative
mctp_3064VAAXX_5 10358541 951393 9.14% Metastatic Negative
mctp_20E2PAAXX_7 2533757 108578 4.65% Metastatic Negative
mctp_42CJFAAXX_6 8021509 572135 5.49% Metastatic Negative
mctp_20EXPAAXX_5 2277395 104747 4.60% Metastatic Negative
mctp_30CW7AAXX_5 3833469 193479 5.05% Metastatic Negative
mctp_307VGAAXX_1 2430300 141723 5.03% Metastatic Negative
mctp_205K4AAXX_2 2217807 236224 5.00% Metastatic Negative
mctp_20E7PAAXX_2 2339252 113274 4.34% Metastatic Negative
mctp_307YGAAXX_3 3352921 237294 5.42% Metastatic Negative
mctp_20FETAAXX_7 2117551 103001 4.02% Metastatic Negative
mctp_20E2PAAXX_8 2620052 71719 4.33% Metastatic Negative
mctp_30CW7AAXX_7 8952621 260253 5.07% Metastatic Negative
1417627939 114148345 0.07%
TABLE-US-00002 TABLE 2 Merge intron- Join Filter Classification
redundant Informatic transcript intronic UCSC Chromosome
Cuffcompare tree filter transcripts filters fragments pre-mRNA
Canonical Refseq chr1 759121 272072 12701 5030 4489 3652 2499 3334
chr2 581574 206281 9353 3224 2856 2361 1579 2023 chr3 518621 167071
5706 2917 2560 2053 1312 1816 chr4 329950 103113 5160 2019 1731
1444 977 1238 chr5 380613 126139 5833 2365 2067 1694 1104 1465 chr6
396848 145607 7580 2590 2309 1874 1370 1667 chr7 432152 134051 6432
2355 2132 1703 1326 1583 chr8 308935 97724 4226 1729 1529 1243 848
1210 chr9 359300 122626 4069 1937 1767 1402 1114 1272 chr10 354625
103512 3509 1672 1508 1226 998 1382 chr11 424606 165211 6909 2922
2640 2102 1566 2023 chr12 425280 138650 6872 2653 2373 1858 1233
1668 chr13 159649 68284 3616 1118 908 751 425 549 chr14 261497
123741 4842 1806 1619 1308 855 1102 chr15 291241 108058 5816 1884
1626 1321 1362 1127 chr16 364747 124182 3968 2002 1835 1386 1093
1311 chr17 473261 168469 5581 2780 2582 1950 1480 1907 chr18 144300
49112 2504 785 682 539 377 459 chr19 494738 189411 7209 3543 3239
2269 1668 2314 chr20 217223 70308 3059 1243 1158 907 659 926 chr21
113368 29728 939 495 436 354 306 427 chr22 223385 73509 2401 1156
1068 798 633 771 chrX 222743 94591 4997 1516 1349 1161 959 1841
chrY 15190 4039 272 81 71 59 148 254 Total 8253710 2885489 123554
49822 44534 35415 25921 33669
TABLE-US-00003 TABLE 3 # Uniquely Peak mapped Antibody Antibody
Finder reads (in # Peaks GEO ID File name Pubmed ID used vendor
Used millions) Called GSM353631 VCaP_regular_medium_H3K4me1
20478527 ab8865 Abcam MACS 6.96 23116 GSM353632
VCaP_regular_medium_H3K4me2 20478527 ab7756 Abcam MACS 5.97 74153
GSM353620 VCaP_regular_medium_H3K4me3 20478527 ab8580 Abcam MACS
10.95 30043 GSM353624 VCaP_regular_medium_H3K35me3 20478527 ab9050
Abcam SICER 9.91 29860 GSM353629 VCaP_regular_medium_Ace_H3
20478527 06-599 Millipore MACS 4.76 41971 GSM353622
VCaP_regular_medium_Pan_H3 20478527 ab1791 Abcam MACS 5.91 control
GSM353623 VCaP_regular_medium_Polil 20478527 ab817 Abcam MACS 8.88
16041 GSM353634 LNCaP_regular_medium_H3K4me1 20478527 ab8895 Abcam
MACS 6.19 31109 GSM353635 LNCaP_regular_medium_H3K4me2 20478527
ab7765 Abcam MACS 6.14 62061 GSM353626 LNCaP_regular_medium_H3K4me3
20478527 ab8580 Abcam MACS 10.22 19638 GSM353627
LNCaP_regular_medium_H3K36me3 20478527 ab9050 Abcam SICER 9.15
24932 GSM353628 LNCaP_regular_medium_Ace_H3 20478527 06-599
Millipore MACS 4.75 33211 GSM353617 LNCaP_Ethl_Polil 20478527 ab817
Abcam MACS 1.35 8232 GSM353653 tissue_H3K4me3 20478527 ab8580 Abcam
MACS 11.85 23750
TABLE-US-00004 TABLE 4 Fold change SAM score Category Type Name
Interval (Unlogged) ((r)/(s + s0)) PROTEIN UPREG. TU_0084471_0
chr8: 33380738-34087770 12.75 7.71 NOVEL UPREG. TU_0099865_0 chr8:
128087842-128095202 7.07 7.41 PROTEIN UPREG. TU_0123088_0 chr2:
238147710-238169707 3.01 7.01 ncRNA UPREG. TU_0102832_0 chr9:
78569118-78593537 12.23 6.93 PROTEIN UPREG. TU_0078322_0 chr12:
32280254-32260805 4.52 6.82 ncRNA UPREG. TU_0101270_0 chr21:
41853044-41875166 9.82 6.79 PROTEIN UPREG. TU_0027326_0 chrX:
26874726-17077384 3.31 6.79 PROTEIN UPREG. TU_0092114_0 chr11:
60223535-60239968 7.48 6.65 PROTEIN UPREG. TU_0044448_0 chr13:
51509122-51537893 4.77 6.59 PROTEIN UPREG. TU_0023159_0 chr19:
40224450-40249318 3.59 6.56 PROTEIN UPREG. TU_0092116_0 chr11:
60238919-60239968 7.50 6.44 PROTEIN UPREG. TU_0123090_0 chr2:
238164428-238165452 3.57 6.24 ncRNA UPREG. TU_0046239_0 chr4:
1185645-1201937 5.19 6.22 PROTEIN UPREG. TU_0122750_0 chr2:
231610299-231625861 4.56 6.14 PROTEIN UPREG. TU_0080728_0 chr12:
120142512-120219979 3.26 6.13 PROTEIN UPREG. TU_0123088_0 chr2:
238164428-238165452 4.22 6.12 PROTEIN UPREG. TU_0101111_0 chr21:
36989329-37045253 4.04 6.04 PROTEIN UPREG. TU_0090152_0 chr11:
4965638-4969515 8.38 5.99 PROTEIN UPREG. TU_0101113_0
chr36994126-37045263 3.76 5.98 PROTEIN UPREG. TU_0045026_0 chr13:
94680907-94668260 3.68 5.97 ncRNA UPREG. TU_0101274_0 chr21:
41869930-41870631 8.95 5.88 PROTEIN UPREG. TU_0046239_0 chr4:
1181913-1189142 4.28 5.87 NOVEL UPREG. TU_0064603_0 chr16:
82380933-2394836 7.25 5.84 PROTEIN UPREG. TU_0101308_0 chr21:
42605257-42608791 4.97 5.83 PROTEIN UPREG. TU_0084137_0 chr5:
13981150-13997615 3.91 5.80 PROTEIN UPREG. TU_0084127_0 chr9:
13882635-13892514 4.95 5.79 PROTEIN UPREG. TU_0101119_0 chr22:
37034016-37045253 3.56 5.78 PROTEIN UPREG. TU_0054919_0 chr16:
88188842-88191143 3.48 5.79 PROTEIN UPREG. TU_0126563_0 chr2:
172658361-172662549 27.56 5.88 PROTEIN UPREG. TU_0044977_0 chr13:
94524392-94621526 3.64 5.64 PROTEIN UPREG. TU_0052614_0 chr16:
20542057-20818514 8.85 5.63 NOVEL UPREG. TU_00 _0 chr5:
15839476-15955226 7.46 5.61 PROTEIN UPREG. TU_0060406_0 chr1:
28134091-28158290 3.03 5.61 PROTEIN UPREG. TU_0060407_0 chr1:
28155047-28175469 2.41 5.60 ncRNA UPREG. TU_0100252_0 chr9:
96357168-96369978 5.00 5.58 PROTEIN UPREG. TU_0034719_0 chr14:
73490756-73555773 2.51 5.57 PROTEIN UPREG. TU_0070457_0 chr20:
2258975-2269890 6.49 5.56 NOVEL UPREG. TU_0114240_0 chr2:
1534883-1538193 5.25 5.54 PROTEIN UPREG. TU_0087676_0 chr5:
138643394-138648458 2.75 5.50 PROTEIN UPREG. TU_0084138_0 chr5:
13976388-13981285 4.03 5.48 ncRNA UPREG. TU_0046237_0 chr4:
1162036-1195588 4.29 5.47 ncRNA UPREG. TU_0060421_0 chr1:
38157480-28158290 3.12 5.44 PROTEIN UPREG. TU_0061436_0 chr1:
37954250-37957136 2.66 5.41 PROTEIN UPREG. TU_0044894_0 chr13:
94476096-94752898 2.85 5.38 PROTEIN UPREG. TU_0034720_0 chr14:
73486603-73503474 2.20 5.38 PROTEIN UPREG. TU_0090158_0 chr11:
4965009-4970186 7.37 5.34 PROTEIN UPREG. TU_0061432_0 chr1:
37954250-37958879 2.65 5.31 PROTEIN UPREG. TU_0090268_0 chr11:
6659768-6661138 1.76 5.30 PROTEIN UPREG. TU_0034120_0 chr5:
13743434-13864884 3.59 5.29 PROTEIN UPREG. TU_0043059_0 chr13:
94638351-94639152 2.93 5.28 ncRNA UPREG. TU_0075807_0 chr10:
101676895-101680649 2.61 5.27 PROTEIN UPREG. TU_0078255_0 chr12:
12150992-32421799 3.02 5.26 PROTEIN UPREG. TU_0103019_0 chr9:
87826642-87905011 2.77 5.22 PROTEIN UPREG. TU_0046244_0 chr4:
1185645-1216291 3.51 5.21 PROTEIN UPREG. TU_0075664_0 chr10:
98752046-98935267 4.15 5.20 PROTEIN UPREG. TU_0090949_0 chr11:
24475021-25059245 3.50 5.19 NOVEL UPREG. TU_0099864_0 chr8:
128094589-128103681 3.56 5.17 PROTEIN UPREG. TU_0030278_0 chr8:
106690714-106735138 3.52 5.16 PROTEIN UPREG. TU_0090128_0 chr11:
4654012-4675667 5.26 5.15 PROTEIN UPREG. TU_0017700_0 chr17:
51183394-51209728 2.05 5.13 ncRNA UPREG. TU_0018760_0 chr17:
71645643-71652049 6.41 5.08 PROTEIN UPREG. TU_0018765_0 chr17:
71652262-71747927 5.18 5.06 ncRNA UPREG. TU_0114235_0 chr2:
1521347-1608388 4.22 5.04 PROTEIN UPREG. TU_008 2_0 chr5:
13964456-13969509 4.30 5.03 NOVEL UPREG. TU_0049368_0 chr4:
106772318-106772770 3.40 5.03 PROTEIN UPREG. TU_0115204_0 chr2:
27175274-27195587 2.37 4.99 PROTEIN UPREG. TU_0115205_0 chr2:
27163593-27178264 2.49 4.98 PROTEIN UPREG. TU_0062443_0 chr1:
46418568-46424753 1.95 4.96 PROTEIN UPREG. TU_0072027_0 chr20:
35064872-36007156 3.91 4.95 ncRNA UPREG. TU_0086706_0 chr5:
116818427-116835522 2.91 4.92 PROTEIN UPREG. TU_0084136_0 chr5:
13972327-13976415 3.37 4.91 PROTEIN UPREG. TU_0042761_0 chr13:
23200813-23363662 3.54 4.90 PROTEIN UPREG. TU_0114168_0 chr15:
99658271-99847175 2.25 4.89 ncRNA UPREG. TU_0018764_0 chr17:
71650143-71652049 6.28 4.86 PROTEIN UPREG. TU_0085832_0 chr5:
76150810-78167655 3.54 4.86 NOVEL UPREG. TU_0030142_0 chr11:
4748677-4760103 12.08 4.86 PROTEIN UPREG. TU_0103018_0 chr9:
87745936-87851451 2.41 4.83 NOVEL UPREG. TU_0096472_0 chr11:
133844590-133862924 6.85 4.82 PROTEIN UPREG. TU_0023229_0 chrX:
70349443-70377690 2.34 4.81 NOVEL UPREG. TU_0084305_0 chr5:
15836315-15947088 5.37 4.78 PROTEIN UPREG. TU_0024934_0 chr19:
54352845-54407356 1.88 4.77 NOVEL UPREG. TU_0095473_0 chr11:
133844590-133852395 6.96 4.76 ncRNA UPREG. TU_0101131_0 chr21:
36994125-37041774 3.57 4.74 PROTEIN UPREG. TU_0003239_0 chr7:
7362390-7537552 3.00 4.73 PROTEIN UPREG. TU_0000022_0 chr6:
1567540-2190842 2.14 4.72 PROTEIN UPREG. TU_0085193_0 chr3:
145122471-145183544 2.72 4.72 PROTEIN UPREG. TU_0061439_0 chr1:
37954250-37971671 2.46 4.71 ncRNA UPREG. TU_0096470_0 chr11:
133841573-133880753 6.44 4.70 PROTEIN UPREG. TU_0046219_0 chr4:
993725-995190 3.50 4.69 NOVEL UPREG. TU_0078788_0 chr12:
32393283-32405731 2.47 4.67 PROTEIN UPREG. TU_0101115_0 chr21:
37000839-37005920 3.31 4.67 NOVEL UPREG. TU_0099884_0 chr8:
128301493-128307578 2.65 4.56 PROTEIN UPREG. TU_0008459_0 chr7:
23885581-23708358 1.70 4.54 PROTEIN UPREG. TU_0042767_0 chr13:
23186656-23204319 4.82 4.64 PROTEIN UPREG. TU_0061430_0 chr1:
37930752-37957012 2.30 4.64 PROTEIN UPREG. TU_0079451_0 chr12:
52696814-52736068 3.77 4.64 PROTEIN UPREG. TU_0069545_0 chr2:
226711356-226712534 2.36 4.63 PROTEIN UPREG. TU_0045837_0 chr1:
113151233-118151444 3.73 4.61 PROTEIN UPREG. TU_0101138_0 chr21:
18994126-37804810 3.54 4.61 PROTEIN UPREG. TU_0049362_0 chr4:
106693102106771686 3.06 4.58 PROTEIN UPREG. TU_0055044_0 chr16:
88589437-88613428 2.23 4.55 PROTEIN UPREG. TU_0038605_0 chr3:
52689830-52704551 1.54 4.55 ncRNA UPREG. TU_0062653_0 chr1:
51756544-51799759 2.52 4.54 PROTEIN UPREG. TU_0080359_0 chr12:
63512292-65558861 1.87 4.53 PROTEIN UPREG. TU_0012481_0 chr7:
111155336-111217889 2.04 4.52 PROTEIN UPREG. TU_0076356_0 chr10:
116970327-116995963 10.34 4.52 PROTEIN UPREG. TU_0099892_0 chr8:
128817416-128822629 2.33 4.51 ncRNA UPREG. TU_0060484_0 chr1:
38766931-28707187 2.53 4.51 PROTEIN UPREG. TU_0046732_0 chr4:
1147069-1175181 2.75 4.50 PROTEIN UPREG. TU_0107858_0 chr22:
40664589-40573116 2.27 4.50 PROTEIN UPREG. TU_0042794_0 chr13:
23228583-25228659 3.47 4.49 PROTEIN UPREG. TU_0057850_0 chr1:
1523259-1525323 2.80 4.48 PROTEIN UPREG. TU_0023156_0 chr1:
40109515-40127909 2.56 4.48 PROTEIN UPREG. TU_0102821_0 chr9:
78263916-78312152 2.98 4.48 PROTEIN UPREG. TU_0081653_0 chr12:
108638297-108780791 2.90 4.47 PROTEIN UPREG. TU_0049370_0 chr4:
106776991-106847637 2.15 4.47 PROTEIN UPREG. TU_0047672_0 chr4:
41807710-41840313 2.51 4.47 PROTEIN UPREG. TU_0114959_0 chr2:
24865850-24869912 1.68 4.46 PROTEIN UPREG. TU_0037043_0 chr3:
13332730-13436812 1.77 4.46 PROTEIN UPREG. TU_0087443_0 chr5:
135257637-135247034 4.09 4.46 PROTEIN UPREG. TU_0086635_0 chr5:
114489075-114543906 2.02 4.43 PROTEIN UPREG. TU_0107859_0 chr22:
40664589-40665721 2.38 4.42 NOVEL UPREG. TU_0106548_0 chr22:
22209111-22212855 6.49 4.42 PROTEIN UPREG. TU_0067165_0 chr3:
160797907-160845987 1.81 4.40 PROTEIN UPREG. TU_0020146_0 chr10:
3728970-3737293 2.53 4.39 PROTEIN UPREG. TU_0107642_0 chr22:
39046992-39047479 1.69 4.38 PROTEIN UPREG. TU_0016185_0 chr17:
31415814-31422953 3.69 4.38 NOVEL UPREG. TU_0104717_0 chr9:
130697833-130698832 2.79 4.36 PROTEIN UPREG. TU_0052105_0 chr16:
4785874-4786488 2.99 4.36 PROTEIN UPREG. TU_0058663_0 chr1:
21795295-21850855 1.99 4.35 PROTEIN UPREG. TU_0108056_0 chr22:
43527112-46638770 1.74 4.34 PROTEIN UPREG. TU_0098781_0 chr11:
67151991-67154057 2.48 4.33 PROTEIN UPREG. TU_0085924_0 chr5:
126233852-126241807 2.89 4.32 PROTEIN UPREG. TU_0048191_0 chr4:
72423780-72424347 2.93 4.32 PROTEIN UPREG. TU_0034727_0 chr14:
73508223-73508442 2.29 4.32 PROTEIN UPREG. TU_0096297_0 chr11:
128342286-128353900 1.84 4.31 PROTEIN UPREG. TU_0007829_0 chr2:
3625233-4275129 4.39 4.30 PROTEIN UPREG. TU_0116252_0 chr2:
47449510-47467636 1.93 4.30 PROTEIN UPREG. TU_0115216_0 chr2:
27179274-27177799 2.02 4.27 PROTEIN UPREG. TU_0018409_0 chr17:
66013419-65059811 2.02 4.26 PROTEIN UPREG. TU_0090847_0 chr8:
126511614-126519830 2.75 4.25 PROTEIN UPREG. TU_0035182_0
chr14:81062781-81063412 2.22 4.25 PROTEIN UPREG. TU_0040936_0 chr3:
155391785-155458298 2.10 4.26 PROTEIN UPREG. TU_0027558_0 chrX:
23595491-23614435 1.66 4.25 PROTEIN UPREG. TU_0076460_0 chr10:
121248954-121292235 1.68 4.24 PROTEIN UPREG. TU_0067170_0 chr1:
160826739-1608726994 2.10 4.23 PROTEIN UPREG. TU_0303050_0 chr9:
89409881-89512477 2.30 4.23 PROTEIN UPREG. TU_0112868_0 chr19:
77590455-77402342 1.55 4.23 PROTEIN UPREG. TU_0090960_0 chr11:
25059388-25060757 3.85 4.23 PROTEIN UPREG. TU_0072165_0 chr20:
40142077-40204030 4.69 4.22 PROTEIN UPREG. TU_0044687_0 chr13:
74756644-74954891 2.04 4.21 ncRNA UPREG. TU_0096477_0 chr11:
133479414-133850753 4.43 4.21 PROTEIN UPREG. TU_0093947_0 chr11:
68208575-68215218 1.41 4.20 PROTEIN UPREG. TU_0103253_0 chr9:
96405246-96442373 1.69 4.20 PROTEIN UPREG. TU_0091863_0 chr11:
57008498-57039966 2.69 4.20 PROTEIN UPREG. TU_0106199_0 chr22:
18300042-15014411 3.94 4.20 NOVEL UPREG. TU_0090140_0 chr11:
4748163-4759145 6.33 4.20 PROTEIN UPREG. TU_0103051_0 chr9:
89302442-89405899 2.37 4.19 NOVEL UPREG. TU_0078290_0 chr12:
32594534-32410838 3.20 4.19 PROTEIN UPREG. TU_0029336_0 chrX:
70869659-70712461 1.70 4.18 PROTEIN UPREG. TU_0092155_0 chr11:
60871597-60886554 1.80 4.18 PROTEIN UPREG. TU_0095597_0 chr11:
114549577-114880335 1.75 4.18 PROTEIN UPREG. TU_0082724_0 chr12:
120230545-120274615 1.42 4.17 PROTEIN UPREG. TU_0079770_0 chr12:
55040665-55042824 4.25 4.16 PROTEIN UPREG. TU_0000263_0 chr6:
4060929-4080831 1.56 4.16 NOVEL UPREG. TU_0040394_0 chr3:
133418532-133441282 3.46 4.16 PROTEIN UPREG. TU_0066594_0 chr1:
15424543-154257368 1.40 4.15 PROTEIN UPREG. TU_0099852_0 chr8:
126515081-126519830 2.81 4.15 PROTEIN UPREG. TU_0100363_0 chr8:
144891741-144899588 2.24 4.14 PROTEIN UPREG. TU_0095461_0 chr11:
133751095-133757235 2.10 4.13 ncRNA UPREG. TU_0044488_0 chr13:
51641093-51641310 2.76 4.13 PROTEIN UPREG. TU_0048990_0 chr4:
95592056-95804933 2.30 4.13 NOVEL UPREG. TU_0078293_0 chr12:
12396393-32414822 2.90 4.13 PROTEIN UPREG. TU_0046202_0 chr4:
991841-1010686 2.57 4.12 PROTEIN UPREG. TU_0091866_0 chr11:
57008498-57010253 2.54 4.12 PROTEIN UPREG. TU_0011133_0 chr7:
94378726-94759741 1.77 4.12 PROTEIN UPREG. TU_0122941_0 chr2:
234410713-234427931 3.28 4.12 PROTEIN UPREG. TU_0084131_0 chr5:
13929880-13953380 2.62 4.12 NOVEL UPREG. TU_0084142_0 chr5:
14017046-14021379 3.59 4.11 PROTEIN UPREG. TU_0087955_0 chr5:
140931545-140931565 2.00 4.10 PROTEIN UPREG. TU_0085953_0 chr5:
79410392-79410389 3.35 4.10 PROTEIN UPREG. TU_0022288_0 chr19:
18357973-18360121 2.75 4.09 PROTEIN UPREG. TU_0085951_0 chr5:
79366959-79414885 3.01 4.09 PROTEIN UPREG. TU_0060849_0 chr1:
32572021-32574435 1.81 4.09 PROTEIN UPREG. TU_0087441_0 chr5:
134934290-134942617 2.74 4.09 PROTEIN UPREG. TU_0042725_0 chr13:
23148223-23200551 4.96 4.09 PROTEIN UPREG. TU_0039018_0 chr3:
66510505-66634168 1.68 4.08 PROTEIN UPREG. TU_0096299_0 chr11:
128340164-128347506 1.70 4.07 PROTEIN UPREG. TU_0022290_0 chr19:
18357973-18359195 2.64 4.07 PROTEIN UPREG. TU_0100684_0 chr8:
146190487-146191030 1.89 4.06 PROTEIN UPREG. TU_0042974_0 chr13:
26148671-2614967 2.81 4.06 NOVEL UPREG. TU_0084308_0 chr5:
15938753-15949124 4.08 4.06 NOVEL UPREG. TU_0082746_0 chr12:
120197102-120197416 4.97 4.06 PROTEIN UPREG. TU_0014355_0 chr17:
2650561-2887730 1.92 4.05 PROTEIN UPREG. TU_0114110_0 chr15:
99250537-99274351 2.01 4.05 PROTEIN UPREG. TU_0096341_0 chr11:
129534843-129585464 1.54 4.04 PROTEIN UPREG. TU_0052083_0 chr16:
4784094-4805339 2.71 4.04 NOVEL UPREG. TU_0078296_0 chr12:
32394534-32405549 2.92 4.04 PROTEIN UPREG. TU_0084126_0 chr5:
13892443-13903812 3.64 4.03 NOVEL UPREG. TU_0047312_0 chr4:
39217669-39222163 3.83 4.02 PROTEIN UPREG. TU_0008287_0 chr7:
8119340-8268973 1.65 4.02 PROTEIN UPREG. TU_0018937_0 chr17:
73714011-73714967 1.61 4.01 PROTEIN UPREG. TU_0048995_0 chr4:
95805027-95808417 2.47 4.00 PROTEIN UPREG. TU_0038694_0 chr3:
53810226-53855769 2.03 3.99 ncRNA UPREG. TU_0046233_0 chr4:
1202157-1232168 2.45 3.99 PROTEIN UPREG. TU_0019018_0 chr17:
75372094-75381243 2.25 3.98 PROTEIN UPREG. TU_0042326_0 chr :
199123974-199125319 1.77 3.98 PROTEIN UPREG. TU_0099893_0 chr8:
128817416-128819105 2.23 3.98 PROTEIN UPREG. TU_0012491_0 chr7:
111304238-111362856 1.91 3.98 PROTEIN UPREG. TU_0112385_0 chr15:
70816880-70864494 1.71 3.97 PROTEIN UPREG. TU_0042964_0 chr4:
57020861-57038533 1.74 3.97 PROTEIN UPREG. TU_0052565_0 chr1 :
19862784-19409995 1.98 3.96 NOVEL UPREG. TU_0042717_0 chr13:
25149908-23200198 4.95 3.96 PROTEIN UPREG. TU_0017374_0 chr17:
43300055-43404182 1.53 3.96 PROTEIN UPREG. TU_0071058_0 chr20:
20318209-20549154 2.02 3.96 PROTEIN UPREG. TU_0105741_0 chrY:
6971017-6998339 2.20 3.95 PROTEIN UPREG. TU_0018995_0 chr17:
74491566-74517485 1.64 3.94 PROTEIN UPREG. TU_0103055_0 chr9:
89512509-8 513285 1.92 3.93 PROTEIN UPREG. TU_0041139_0 chr3:
171237964-171285906 1.91 3.93 PROTEIN UPREG. TU_0042325_0 chr3:
199124975-199143480 1.74 3.93 PROTEIN UPREG. TU_0020688_0 chr19:
8180054-8237335 1.80 3.93 PROTEIN UPREG. TU_0118314_0 chr2:
90086923-99100654 1.78 3.92 PROTEIN UPREG. TU_0017875_0 chr17:
54652767-54706896 2.33 3.92 PROTEIN UPREG. TU_0037277_0 chr3:
24134438-24511318 1.75 3.92 PROTEIN UPREG. TU_004759 _0 chr4:
40445539-40457235 1.90 3.91 PROTEIN UPREG. TU_0114108_0 chr15:
99235494-99274389 2.00 3.91 ncRNA UPREG. TU_0024530_0 chr19:
50889160-50909766 1.72 3.91 PROTEIN UPREG. TU_0008957_0 chr7:
88308886-38325338 2.62 3.91 PROTEIN UPREG. TU_0043122_0 chr13:
28983555-28989371 1.73 3.90 PROTEIN UPREG. TU_0076644_0 chr10:
127398227-127398596 2.06 3.90 PROTEIN UPREG. TU_0045423_0 chr13:
10055877-100125079 2.02 3.89 PROTEIN UPREG. TU_0045495_0 chr13:
107720446-107737194 2.08 3.88 PROTEIN UPREG. TU_0076648_0
chr10-127412714-127442685 1.64 3.88 NOVEL UPREG. TU_0088857_0 chr5:
172259171-172275517 1.69 3.87 NOVEL UPREG. TU_0044453_0 chr13:
51505777-51524522 2.95 3.86 NOVEL UPREG. TU_0047380_0 chr4:
39217641-39222163 3.43 3.86 PROTEIN UPREG. TU_0100838_0 chr21:
30508275-30510244 2.43 3.86 NOVEL UPREG. TU_0106544_0 chr22:
22210421-22220506 4.27 3.85 ncRNA UPREG. TU_0100275_0 chr8:
144520506-144537551 2.11 3.85 PROTEIN UPREG. TU_0057466_0 chr18:
72853744-72866791 1.58 3.84 PROTEIN UPREG. TU_0040010_0 chr3:
126331839-126412928 2.16 3.84 PROTEIN UPREG. TU_0042800_0 chr13:
23360816-23370548 2.73 3.84 PROTEIN UPREG. TU_0112501_0 chr2:
74065748-74174193 1.71 3.83
PROTEIN UPREG. TU_0053389_0 chr1 : 45673980-45701001 2.66 3.83
PROTEIN UPREG. TU_0087944_0 chr11: 140874777-140978925 1.47 3.83
PROTEIN UPREG. TU_0017393_0 chr17: 43389397-43390800 1.90 3.82
PROTEIN UPREG. TU_0008919_0 chr7: 38257158-38271020 1.93 3.82
PROTEIN UPREG. TU_0088393_0 chr14: 50259793-50367616 1.51 3.82
PROTEIN UPREG. TU_0049911_0 chr4: 139304784-139382952 2.48 3.82
PROTEIN UPREG. TU_0024366_0 chr19: 50100808-50104487 1.88 3.82
PROTEIN UPREG. TU_0070109_0 chr1: 243979271-244159914 1.56 3.81
PROTEIN UPREG. TU_0120975_0 chr2: 182104651-182107832 1.89 3.80
NOVEL UPREG. TU_0044933_0 chr18: 94765992-94760688 2.52 3.80
PROTEIN UPREG. TU_0103689_0 chr9: 111019219-111122750 1.75 3.80
PROTEIN UPREG. TU_0096460_0 chr11: 133734857-133786962 2.09 3.79
PROTEIN UPREG. TU_0071115_0 chr20: 24934888-24986948 1.48 3.79
PROTEIN UPREG. TU_0093788_0 chr11: 67153661-67153870 2.48 3.79
PROTEIN UPREG. TU_0047591_0 chr4: 40457999-40508855 1.79 3.79
PROTEIN UPREG. TU_0112336_0 chr15: 70880765-70838345 1.83 3.78
PROTEIN UPREG. TU_0086664_0 chr1: 154481433-154485049 2.29 3.78
PROTEIN UPREG. TU_0018812_0 chr17: 72119376-72151549 3.38 3.78
PROTEIN UPREG. TU_0110225_0 chr15: 48510091-48912722 3.60 3.78
ncRNA UPREG. TU_0054545_0 chr16: 79431010-79431652 10.28 3.78
PROTEIN UPREG. TU_0107643_0 chr22: 39072496-39093168 1.36 3.78
PROTEIN UPREG. TU_0025230_0 chr19: 55992773-56000199 1.86 3.78
PROTEIN UPREG. TU_0012480_0 chr7: 111153704-111155311 1.81 3.77
PROTEIN UPREG. TU_0070821_0 chr20: 8997167-9409281 1.64 3.77
PROTEIN UPREG. TU_0103873_0 chr9: 115151636-115178183 1.52 3.77
PROTEIN UPREG. TU_0018813_0 chr17: 72128611-72133119 3.56 3.76
NOVEL UPREG. TU_0112004_0 chr18: 67644390-67650387 3.56 3.76
PROTEIN UPREG. TU_0043118_0 chr13: 28981555-29067829 1.76 3.76
NOVEL UPREG. TU_0112003_0 chr15: 67645590-67775246 3.12 3.76 NOVEL
UPREG. TU_0060448_0 chr1: 28438629-28450150 2.23 3.75 PROTEIN
UPREG. TU_0122972_0 chr2: 236068012-236482693 1.69 3.75 NOVEL
UPREG. TU_0106545_0 chr22: 22218478-22219162 3.99 3.74 PROTEIN
UPREG. TU_0087288_0 chr5: 133755241-133766074 1.85 3.74 ncRNA
UPREG. TU_0025312_0 chr19: 57059515-57145170 1.89 3.74 PROTEIN
UPREG. TU_0079679_0 chr12: 54760142-54783545 1.58 3.73 PROTEIN
UPREG. TU_0074564_0 chr10: 64241786-64246112 2.62 3.73 PROTEIN
UPREG. TU_0106189_0 chr22: 18235213-18328816 1.82 3.73 PROTEIN
UPREG. TU_0078994_0 chr12: 49412412-49428706 1.41 3.72 ncRNA UPREG.
TU_0003229_0 chr6: 41598975-41621874 2.05 3.72 PROTEIN UPREG.
TU_0040937_0 chr3: 155439710-155458293 1.96 3.72 PROTEIN UPREG.
TU_0040093_0 chr5: 128880751-128874336 1.87 3.72 NOVEL UPREG.
TU_0106542_0 chr22: 22213315-22220505 3.77 3.71 PROTEIN UPREG.
TU_0019375_0 chr17: 77608812-77816980 1.63 3.71 PROTEIN UPREG.
TU_0042568_0 chr15: 20264762-20334986 1.85 3.71 PROTEIN UPREG.
TU_0103386_0 chr9: 99895734-99118148 1.89 3.71 PROTEIN UPREG.
TU_0030004_0 chrX: 100534013-100534540 1.84 3.71 NOVEL UPREG.
TU_0089906_0 chr11: 1042845-1045785 2.94 3.71 NOVEL UPREG.
TU_0089014_0 chr9: 176014905-176015351 2.01 3.71 ncRNA UPREG.
TU_0056173_0 chr18: 22525074-22557627 3.31 3.70 PROTEIN UPREG.
TU_0052880_0 chr16: 28393117-28411069 1.48 3.70 PROTEIN UPREG.
TU_0100355_0 chr8: 144884230-144910177 2.00 3.69 PROTEIN UPREG.
TU_0096216_0 chr11: 125271293-125271517 2.08 3.69 PROTEIN UPREG.
TU_0092161_0 chr11: 60884289-60892364 1.99 3.68 PROTEIN UPREG.
TU_0086926_0 chr5: 126241958-126394149 2.27 3.68 NOVEL UPREG.
TU_0088230_0 chr5: 148864170-148864752 1.94 3.68 ncRNA UPREG.
TU_0099940_0 chr8: 129855546-129182684 1.61 3.68 PROTEIN UPREG.
TU_0089017_0 chr5: 176222085-176240501 10.21 3.67 PROTEIN UPREG.
TU_0078586_0 chr12: 46643629-46648944 1.47 3.67 PROTEIN UPREG.
TU_0053467_0 chr16: 51028455-51138080 2.19 3.67 PROTEIN UPREG.
TU_0089452_0 chr5: 179258704-179258997 1.62 3.67 PROTEIN UPREG.
TU_0076329_0 chr10: 115501382-115531028 2.60 3.67 PROTEIN UPREG.
TU_0047688_0 chr4: 42105164-42354144 1.68 3.67 PROTEIN UPREG.
TU_0059142_0 chr1: 16203274-16206548 12.41 3.67 PROTEIN UPREG.
TU_0116906_0 chr2: 63155968-53138462 2.81 3.66 PROTEIN UPREG.
TU_0000154_0 chr6: 3063923-3099152 1.53 3.66 PROTEIN UPREG.
TU_0088782_0 chr5: 170625426-170659598 1.78 3.66 NOVEL UPREG.
TU_0089905_0 chr11: 1042845-1045785 2.77 3.66 PROTEIN UPREG.
TU_0101704_0 chr9: 3265495-3516005 2.33 3.64 ncRNA UPREG.
TU_0044897_0 chr15: 94746498-94760688 2.17 3.64 PROTEIN UPREG.
TU_0071059_0 chr20: 20549245-20641260 2.39 3.64 ncRNA UPREG.
TU_0046268_0 chr4: 1199698-1211108 1.93 3.63 PROTEIN UPREG.
TU_0071601_0 chr20:32827590-32828002 1.75 3.62 PROTEIN UPREG.
TU_0100712_0 chr21: 15258179-15359100 2.14 3.62 PROTEIN UPREG.
TU_0092158_0 chr11: 60885030-60893249 1.45 3.62 PROTEIN UPREG.
TU_0091402_0 chr11: 46255779-46299542 1.71 3.62 PROTEIN UPREG.
TU_0039019_0 chr3: 66376322-66514060 1.50 3.62 PROTEIN UPREG.
TU_0100378_0 chr8: 144899799-144900640 2.00 3.62 NOVEL UPREG.
TU_0112025_0 chr15: 67780574-67782345 3.42 3.62 PROTEIN UPREG.
TU_0106031_0 chr22: 16336630-16412806 2.01 3.62 PROTEIN UPREG.
TU_0050785_0 chr4: 174895560-174453821 2.38 3.61 PROTEIN UPREG.
TU_0058834_0 chr1: 11768665-11783670 1.50 3.61 PROTEIN UPREG.
TU_0039496_0 chr3: 106753939-106754201 1.99 3.61 ncRNA UPREG.
TU_0098397_0 chr8: 69379259-69406175 2.73 3.61 PROTEIN UPREG.
TU_0017847_0 chr17: 54188675-54413808 2.82 3.61 PROTEIN UPREG.
TU_0108299_0 chr22: 49267227-49270226 2.03 3.60 PROTEIN UPREG.
TU_0076846_0 chr10: 135042714-155056676 2.27 3.59 PROTEIN UPREG.
TU_0096351_0 chr11: 129611827-129689996 1.61 3.59 PROTEIN UPREG.
TU_0019298_0 chr17: 77242472-77300154 1.51 3.59 PROTEIN UPREG.
TU_0057465_0 chr18: 72830973-729737 9 1.55 3.59 PROTEIN UPREG.
TU_0013475_0 chr2: 148137800-148212387 1.74 3.59 PROTEIN UPREG.
TU_00 1426_0 chr6: 28688044-28662198 2.58 3.59 NOVEL UPREG. TU_01
541_0 chr22: 22209111-22219162 4.02 3.58 PROTEIN UPREG.
TU_0071803_0 chr10: 19005564-19007053 1.94 3.58 PROTEIN UPREG.
TU_0010100_0 chr3: 129253916-129269610 1.39 3.58 PROTEIN UPREG.
TU_0001432_0 chr6: 28978594-28999755 1.33 3.58 PROTEIN UPREG.
TU_0076643_0 chr10: 127398227-127407663 1.73 3.57 PROTEIN UPREG.
TU_0089137_0 chr5: 176814485-176815986 1.93 3.57 PROTEIN UPREG.
TU_0098700_0 chr8: 87 06988-82333612 1.76 3.57 PROTEIN UPREG.
TU_0093785_0 chr11: 67186209-67198838 3.74 3.57 NOVEL UPREG.
TU_0056163_0 chr18: 22477042-22477665 3.05 3.57 PROTEIN UPREG.
TU_0067222_0 chr1: 164063363-194147501 1.63 3.57 PROTEIN UPREG.
TU_0052172_0 chr16: 8799176-8790379 1.61 3.57 PROTEIN UPREG.
TU_0008350_0 chr7: 16852301-16712672 1.45 3.57 PROTEIN UPREG.
TU_0035610_0 chr14: 935 0687-93582188 2.08 3.56 PROTEIN UPREG.
TU_0000168_0 chr6: 3100128-3102765 2.10 3.56 PROTEIN UPREG.
TU_0019649_0 chr3: 115180992-115164502 1.72 3.56 PROTEIN UPREG.
TU_0052843_0 chr16: 27143818-27187907 1.42 3.56 NOVEL UPREG.
TU_0024950_0 chr19: 54450100-54432968 2.11 3.55 PROTEIN UPREG.
TU_0008504_0 chr7: 24656812-24693891 1.99 3.55 PROTEIN UPREG.
TU_0061102_0 chr1: 35571678-35795597 1.44 3.55 PROTEIN UPREG.
TU_0032850_0 chr14: 36736878: 36788106 2.36 3.55 ncRNA UPREG.
TU_0045241_0 chr4: 1198292-1167180 2.53 3.55 NOVEL UPREG. TU_00
499_0 chr7: 24236191-24236455 5.44 3.54 PROTEIN UPREG. TU_0100172_0
chr8: 142471307-142511866 1.79 3.54 NOVEL UPREG. TU_0085543_0 chr5:
110311813-110312092 1.53 3.53 PROTEIN UPREG. TU_0072450_0 chr20:
44161989 -44747359 1.83 3.53 NOVEL UPREG. TU_0094972_0 chr15:
94755980-94759735 2.15 3.53 PROTEIN UPREG. TU_0093950_0 chr11: 6
21474 -68215218 1.49 3.53 PROTEIN UPREG. TU_0006239_0 chr6:
13864933 -133671427 2.22 3.53 PROTEIN UPREG. TU_0063894_0 chr1:
150944684-150070988 1.54 3.52 PROTEIN UPREG. TU_0078675_0 chr12:
47602047-47602939 1.58 3.52 PROTEIN UPREG. TU_0052150_0 chr16:
8799176-65-64674 1.42 3.52 NOVEL UPREG. TU_0112011_0 chr15:
67762926-67783593 2.66 3.52 PROTEIN UPREG. TU_0041581_0 chr3:
185450132-185459240 1.77 3.52 PROTEIN UPREG. TU_0017269_0 chr17:
42127174-421 9979 1.59 3.52 PROTEIN UPREG. TU_010138_0 chr6:
94055563-94056963 1.61 3.52 PROTEIN UPREG. TU_0078683_0 chr12:
47503989-47604485 1.69 3.52 PROTEIN UPREG. TU_0099209_0 chr11:
6453771-6453210 1.44 3.51 ncRNA UPREG. TU_004519 _0 chr15:
97851959-97852689 1.98 3.51 PROTEIN UPREG. TU_0050499_0 chr4:
159862572-156862939 1.82 3.51 PROTEIN UPREG. TU_0088025_0 chr5:
142130154-142254088 1.89 3.51 PROTEIN UPREG. TU_0052554_0 chr16:
10329285-19424714 1.78 3.51 PROTEIN UPREG. TU_0085663_0 chr5:
70918890-75990273 2.39 3.51 PROTEIN UPREG. TU_0101238_0 chr21:
41610496-41851888 1.89 3.50 PROTEIN UPREG. TU_0098659_0 chr8:
82355436-82355877 4.15 3.49 PROTEIN UPREG. TU_0100271_0 chr8:
144522379-144537551 1.33 3.49 PROTEIN UPREG. TU_0013258_0 chr7:
139750340-139773086 1.85 3.49 PROTEIN UPREG. TU_0122559_0 chr2:
224338108-224338327 2.32 3.49 PROTEIN UPREG. TU_0062947_0 chr1:
212567070-212567723 1.74 3.48 PROTEIN UPREG. TU_0101300_0 chr21:
42512421-42593934 1.60 3.48 PROTEIN UPREG. TU_0105268_0 chr3:
1382318731-138277254 1.49 3.47 PROTEIN UPREG. TU_0080269_0 chr12:
62524730-62664317 2.05 3.47 PROTEIN UPREG. TU_0051992_0 chr6:
31939105-31955076 1.56 3.47 PROTEIN UPREG. TU_0018485_0 chr17:
76458432-70490451 1.58 3.47 ncRNA UPREG. TU_0050493_0 chr1:
28705947-28706605 1.60 2.46 PROTEIN UPREG. TU_0085975_0 chr5:
79478814-79495113 1.91 3.46 PROTEIN UPREG. TU_0018919_0 chr17:
73678343-73714570 1.48 3.46 ncRNA UPREG. TU_0054534_0 chr16:
79404014-79431652 9.85 3.46 PROTEIN UPREG. TU_0076107_0 chr10:
104464315-104488075 1.67 3.45 ncRNA UPREG. TU_0069658_0 chr1:
229724782-229731269 1.75 3.45 NOVEL UPREG. TU_0120387_0 chr2:
170267824-170281385 2.10 3.45 PROTEIN UPREG. TU_0013665_0 chr17:
24073407-24077926 1.52 3.45 ncRNA UPREG. TU_0070414_0 chr20:
3254059-1303172 1.65 3.45 NOVEL UPREG. TU_0072624_0 chr20:
47335522-47338977 1.65 3.45 PROTEIN UPREG. TU_0012495_0 chr7:
111373031-111411626 2.29 3.45 PROTEIN UPREG. TU_0076659_0 chr10:
177514501-127576128 1.31 3.45 PROTEIN UPREG. TU_0088525_0 chr5:
156525701-156755173 1.53 3.45 PROTEIN UPREG. TU_0046096_0 chr4:
759449-809939 2.01 3.44 ncRNA UPREG. TU_0074332_0 chr10:
43420869-43421283 1.52 3.44 PROTEIN UPREG. TU_0082983_0 chr12:
121778239-121779189 2.65 3.44 PROTEIN UPREG. TU_0008361_0 chr2:
16750923-16790805 1.58 3.44 PROTEIN UPREG. TU_0081443_0 chr1:
38032067-38039550 1.67 3.44 PROTEIN UPREG. TU_0042715_0 chr13:
25148223-23204319 3.68 3.43 ncRNA UPREG. TU_0119128_0 chr2:
118310197-118313068 1.62 3.43 PROTEIN UPREG. TU_0112349_0 chr15:
70834440-70835126 1.67 3.43 PROTEIN UPREG. TU_0027543_0 chrX:
21921233-21922374 2.48 3.43 PROTEIN UPREG. TU_0082552_0 chr1:
47889058-47552320 1.83 3.43 ncRNA UPREG. TU_0080791_0 chr4:
174322695-174323924 2.13 3.41 PROTEIN UPREG. TU_0048346_0 chr4:
77175264-77176185 2.48 3.41 NOVEL UPREG. TU_0093068_0 chr11:
64956618-64961189 2.13 3.41 PROTEIN UPREG. TU_0033869_0 chr14:
60248258-60250801 1.71 3.41 PROTEIN UPREG. TU_0000031_0 chr6:
2190031-2190908 2.44 3.41 PROTEIN UPREG. TU_0082131_0 chr12:
111152572-111152227 1.89 3.40 PROTEIN UPREG. TU_0038169_0 chr3:
49035494-49041923 1.35 3.40 NOVEL UPREG. TU_0044898_0 chr13:
94753009-94760688 2.11 3.40 PROTEIN UPREG. TU_0089144_0 chrS:
176814485-176815986 1.86 3.40 PROTEIN UPREG. TU_0094504_0 chr11:
74812477-74817273 2.40 3.40 PROTEIN UPREG. TU_0035633_0 chr14:
94304291-94305127 2.17 3.40 PROTEIN UPREG. TU_0085819_0 chrS:
75734806-76039614 1.64 3.40 PROTEIN UPREG. TU_0061431_0 chr1:
37961347-37973585 2.62 3.40 NOVEL UPREG. TU_0078299_0 chr12:
32290896-32292169 3.67 3.39 PROTEIN UPREG. TU_0004059_0 chr6:
52976578-53054598 1.65 3.39 PROTEIN UPREG. TU_0098927_0 chr8:
95722432-95788870 1.48 3.39 ncRNA UPREG. TU_0013856_0 chr7:
155957953-156090620 2.50 3.39 PROTEIN UPREG. TU_0068377_0 chr1:
201452418-201458956 1.84 3.39 NOVEL UPREG. TU_0101035_0 chr21:
35419563-36421930 1.84 3.39 PROTEIN UPREG. TU_0062957_0 chr1:
54089897-54128073 1.43 3.39 PROTEIN UPREG. TU_0099854_0 chr8:
127633901-127639897 1.65 3.38 PROTEIN UPREG. TU_0048743_0 chr4:
87924751-87955166 1.47 3.38 PROTEIN UPREG. TU_0086478_0 chr5:
102510255-102521832 1.95 3.38 PROTEIN UPREG. TU_0120565_0 chr2:
172672776-172675279 4.31 3.38 PROTEIN UPREG. TU_0122360_0 chr2:
219554051-219557439 2.92 3.38 PROTEIN UPREG. TU_0092154_0 chr11:
60857271-60874474 1.44 3.37 PROTEIN UPREG. TU_0015718_0 chr17:
24095069-24100305 1.64 3.37 PROTEIN UPREG. TU_0039284_0 chr3:
95208686-95249573 2.23 3.37 PROTEIN UPREG. TU_0082089_0 chr12:
111082307-111187476 1.44 3.37 PROTEIN UPREG. TU_0035148_0 chr14:
81009021-81069951 1.64 3.37 PROTEIN UPREG. TU_0054849_0 chr16:
87403253-87406669 1.47 3.37 PROTEIN UPREG. TU_0113376_0 chr15:
87432650-87545107 2.13 3.36 PROTEIN UPREG. TU_0019481_0 chr17:
77998514-77999441 1.55 3.36 PROTEIN UPREG. TU_0007004_0 chr6:
158396021-158440190 1.47 3.36 PROTEIN UPREG. TU_0092190_0 chr11:
60876795-60877493 1.85 3.36 ncRNA UPREG. TU_0001996_0 chr6:
31941546-31959679 1.43 3.36 NOVEL UPREG. TU_0066689_0 chr1:
154509233-154510967 1.61 3.36 PROTEIN UPREG. TU_0035151_0 chr14:
81015445-81021875 2.00 3.35 PROTEIN UPREG. TU_0092866_0 chr11:
55975211-63975675 3.20 3.35 PROTEIN UPREG. TU_0050482_0 chr4:
156807332-156877628 1.69 3.35 PROTEIN UPREG. TU_0022391_0 chr19:
19076718-19094443 1.60 3.35 PROTEIN UPREG. TU_0048729_0 chr4:
87734463-87924734 1.74 3.35 PROTEIN UPREG. TU_0103472_0 chr9:
100534124-100570357 1.61 3.35 PROTEIN UPREG. TU_0087465_0 chr5:
136431191-136431490 2.47 3.35 PROTEIN UPREG. TU_0058833_0 chr1:
11768665-11788581 1.45 3.34 PROTEIN DOWNREG. TU_0009047_0 chr7:
41967123-41970103 0.65 -3.35 PROTEIN DOWNREG. TU_0020039_0 chr19:
2948637-2980244 0.65 -3.36 PROTEIN DOWNREG. TU_0024046_0 chr19:
47194316-47201741 0.53 -3.36 PROTEIN DOWNREG. TU_0120035_0 chr:
154042114-154043553 0.49 -3.36 PROTEIN DOWNREG. TU_0014542_0 chr17:
4790024-47790984 0.77 -3.36 PROTEIN DOWNREG. TU_0058703_0 chr1:
10857547-10613394 0.66 -3.37 NOVEL DOWNREG. TU_0084922_0 chrS:
44337219-44338127 0.51 -3.37 PROTEIN DOWNREG. TU_0067333_0 chr1:
167362572-167539064 0.68 -3.37 PROTEIN DOWNREG. TU_0030086_0 chrX:
101794939-101798995 0.64 -3.37 PROTEIN DOWNREG. TU_0031101_0 chrX:
134247418-134254372 0.69 -3.37 PROTEIN DOWNREG. TU_0063762_0 chr1:
87666944-87583813 0.66 -3.38 PROTEIN DOWNREG. TU_0107584_0 chr22:
38075931-38123808 0.66 -3.38 PROTEIN DOWNREG. TU_0102296_0 chr9:
34979701-34988409 0.57 -3.38 PROTEIN DOWNREG. TU_0038485_0 chr3:
51981847-51958558 0.65 -3.38 PROTEIN DOWNREG. TU_0062948_0 chr1:
53744574-53746867 0.48 -3.38 PROTEIN DOWNREG. TU_0092656_0 chr11:
63282470-63288729 0.73 -3.38 PROTEIN DOWNREG. TU_0035606_0 chr14:
95470258-93500717 0.58 -3.38 PROTEIN DOWNREG. TU_0053588_0 chr18:
10470831-10478690 0.58 -3.38 PROTEIN DOWNREG. TU_0056465_0 chr18:
41558112-41584622 0.49 -3.39 PROTEIN DOWNREG. TU_0002739_0 chr6:
35321958-35328561 0.55 -3.39 PROTEIN DOWNREG. TU_0030147_0 chrx:
102727067-102729284 0.65 -3.39 NOVEL DOWNREG. TU_0030209_0 chrx:
103250961-103253228 0.68 -3.39 ncRNA DOWNREG. TU_0068206_0 chr1:
200132176-200134973 0.60 -3.39 PROTEIN DOWNREG. TU_0081627_0 chr12:
108186419-108190411 0.63 -3.40 PROTEIN DOWNREG. TU_0088194_0 chr2:
200132176-200182322 0.59 -3.40 PROTEIN DOWNREG. TU_0049308_0 chr4:
104220026-104220361 0.46 -3.40 NOVEL DOWNREG. TU_0068431_0 chr1:
202350966-202363482 0.62 -3.40 PROTEIN DOWNREG. TU_0073506_0 chr10:
7630096-7723984 0.60 -3.40 PROTEIN DOWNREG. TU_0054695_0 chr16:
83411108-83499914 0.62 -3.40 PROTEIN DOWNREG. TU_0012556_0 chr7:
115934290-115935899 0.50 -3.41 PROTEIN DOWNREG. TU_0018647_0 chr17:
71259157-71294839 0.74 -3.41 NOVEL DOWNREG. TU_0030577_0 chrX:
118036531-118035860 0.43 -3.41 PROTEIN DOWNREG. TU_0089981_0 chr11:
2248339-2247566 0.52 -3.41 PROTEIN DOWNREG. TU_0000858_0 chr6:
19947236-19950403 0.56 -3.41 PROTEIN DOWNREG. TU_0002212_0 chr8:
32224073-32229328 0.58 -3.41 PROTEIN DOWNREG. TU_0024749_0 chr10:
52937559-52939100 0.58 -3.41 PROTEIN DOWNREG. TU_0102225_0 chr21:
40161189-10181418 0.52 -3.41 ncRNA DOWNREG. TU_0100030_0 chrX:
134893580-134659310 0.41 -3.41 PROTEIN DOWNREG. TU_0102256_0 chr9:
34356684-34366854 0.56 -3.41
PROTEIN DOWNREG. TU_0039040_0 chr3: 69107066-69108860 0.62 -3.42
ncRAN DOWNREG. TU_0115808_0 chr2: 37722515-37725828 0.61 -3.42
PROTEIN DOWNREG. TU_0115807_0 chr2: 37722515-37729828 0.61 -3.42
NOVEL DOWNREG. TU_0038811_0 chr8: 57890130-58970834 0.43 -3.43
PROTEIN DOWNREG. TU_0107000_0 chr22: 29790122-29830660 0.60 -3.43
PROTEIN DOWNREG. TU_0065120_0 chr1: 144274405-144279906 0.53 -3.43
PROTEIN DOWNREG. TU_0065093_0 chr1: 144167535-144181746 0.72 -3.43
PROTEIN DOWNREG. TU_0066887_0 chr1: 158352167-158370985 0.56 -3.44
PROTEIN DOWNREG. TU_0034681_0 chr14: 75248251-73250867 0.61 -3.44
PROTEIN DOWNREG. TU_0064872_0 chr1: 115373945-115394701 0.60 -3.44
PROTEIN DOWNREG. TU_0115146_0 chr2: 26806070-26809827 0.49 -3.44
PROTEIN DOWNREG. TU_0023552_0 chr19: 43433715-43439100 0.52 -3.44
PROTEIN DOWNREG. TU_0013056_0 chr2: 134269121-134268574 0.41 -3.44
PROTEIN DOWNREG. TU_0078015_0 chr12: 21809160-21817495 0.61 -3.45
PROTEIN DOWNREG. TU_0010849_0 chr7: 84462824-84464278 0.41 -3.45
PROTEIN DOWNREG. TU_0018278_0 chr17: 62235564-62237319 0.62 -3.45
PROTEIN DOWNREG. TU_0106896_0 chr22: 28206216-28217370 0.46 -3.46
PROTEIN DOWNREG. TU_0086308_0 chr6: 95168335-95184222 0.54 -3.46
PROTEIN DOWNREG. TU_0053500_0 chr1: 19842799-19857540 0.66 -3.46
PROTEIN DOWNREG. TU_0030156_0 chrX: 102740504-102752163 0.61 -3.46
PROTEIN DOWNREG. TU_0053209_0 chr16: 30815439-60839057 0.45 -3.46
PROTEIN DOWNREG. TU_0102372_0 chr9: 35672000-35681306 0.58 -3.46
PROTEIN DOWNREG. TU_0040491_0 chr3: 134987802-134980829 0.35 -3.46
PROTEIN DOWNREG. TU_0063025_0 chr1: 54832256-54849445 0.56 -3.46
PROTEIN DOWNREG. TU_0016741_0 chr17: 37808007-37818100 0.61 -3.47
PROTEIN DOWNREG. TU_0073672_0 chr12: 65272841-55276238 0.78 -3.47
NOVEL DOWNREG. TU_0072214_0 chr20: 42166331-42122501 0.45 -3.47
PROTEIN DOWNREG. TU_0069254_0 chr3: 223745864-223750945 0.54 -3.48
PROTEIN DOWNREG. TU_0014474_0 chr17: 4410320-4410814 0.34 -3.48
PROTEIN DOWNREG. TU_0082036_0 chr6: 31975375-31977685 0.61 -3.48
ncRNA DOWNREG. TU_0115605_0 chr2: 37722515-37727509 0.64 -3.48
PROTEIN DOWNREG. TU_0106457_0 chr22: 21742726-21732216 0.56 -3.48
PROTEIN DOWNREG. TU_0100880_0 chr21: 32808766-62809639 0.62 -3.48
PROTEIN DOWNREG. TU_0028060_0 chrX: 64873768-64873981 0.59 -3.48
PROTEIN DOWNREG. TU_0183717_0 chr9: 112675354-112576369 0.59 -3.48
PROTEIN DOWNREG. TU_0016732_0 chr17: 37807991-37828819 0.65 -3.48
PROTEIN DOWNREG. TU_0075679_0 chr10: 96987317-970405910 0.65 -3.48
PROTEIN DOWNREG. TU_0108979_0 chr15: 34659121-34889737 0.68 -3.48
PRTEIN DOWNREG. TU_0039868_0 chr3: 123526763-123543198 0.51 -3.48
PROTEIN DOWNREG. TU_0032236_0 chr14: 22839081-22833882 0.61 -3.48
PROTEIN DOWNREG. TU_0103902_0 chr9: 115957988-116128421 0.59 -3.49
PROTEIN DOWNREG. TU_0064251_0 chr6: 71589234-71069482 0.38 -3.49
PROTEIN DOWNREG. TU_0116344_0 chr2: 27568254-27571682 0.64 -3.49
NOVEL DOWNREG. TU_0096307_0 chr11: 7977293-7976927 0.69 -3.49 NOVEL
DOWNREG. TU_0020914_0 chr19: 9718612-9723799 0.47 -3.49 PROTEIN
DOWNREG. TU_0014009_0 chr2: 158823186-158930217 0.48 -3.50 PROTEIN
DOWNREG. TU_0111467_0 chr15: 62817064-62854842 0.58 -3.50 NOVEL
DOWNREG. TU_0058552_0 chr6: 257103852-157120456 0.64 -3.50 PROTEIN
DOWNREG. TU_0016616_0 chr17: 36992068-37034423 0.44 -3.50 PROTEIN
DOWNREG. TU_0109820_0 chr15: 41600571-41611159 0.56 -3.51 PROTEIN
DOWNREG. TU_0083744_0 chr5: 236838-297985 0.58 -3.51 PROTEIN
DOWNREG. TU_0038899_0 chr3: 58465926-58495812 0.58 -3.51 PROTEIN
DOWNREG. TU_0018817_0 chr17: 72185287-72184800 0.61 -3.51 PROTEIN
DOWNREG. TU_0096362_0 chr11: 129779777-129794214 0.56 -3.51 ncRNA
DOWNREG. TU_0104765_0 chr9: 131134480-131144297 0.53 -3.51 PROTEIN
DOWNREG. TU_0047809_0 chr4: 52581019-52582331 0.62 -3.52 PROTEIN
DOWNREG. TU_0114638_0 chr2: 11804195-11654972 0.68 -3.52 PROTEIN
DOWNREG. TU_0110215_0 chr15: 43246574-43254766 0.63 -3.52 PROTEIN
DOWNREG. TU_0117024_0 chr2: 66525747-66653430 0.61 -3.52 PROTEIN
DOWNREG. TU_0109004_0 chr15: 39178588-35180010 0.39 -3.53 PROTEIN
DOWNREG. TU_0114005_0 chr15: 97462760-97493368 0.56 -3.53 PROTEIN
DOWNREG. TU_0079534_0 chr12: 53260191-53268540 0.41 -3.53 PROTEIN
DOWNREG. TU_0068435_0 chr1: 202366748-202385528 0.62 -3.53 PROTEIN
DOWNREG. TU_0014730_0 chr17: 7034460-7061662 0.61 -3.53 PROTEIN
DOWNREG. TU_0111099_0 chr15: 57738640-57756015 0.70 -3.54 PROTEIN
DOWNREG. TU_0079355_0 chr12: 51906987-51912605 0.54 -3.54 PROTEIN
DOWNREG. TU_0107389_0 chr22: 36670710-36671784 0.59 -3.54 PROTEIN
DOWNREG. TU_0105434_0 chr9: 138991774-138996018 0.54 -3.54 ncRNA
DOWNREG. TU_0122441_0 chr2: 220000172-220002664 0.38 -3.54 PROTEIN
DOWNREG. TU_0074041_0 chr10: 29785041-30865975 0.84 -3.55 PROTEIN
DOWNREG. TU_0114819_0 chr2: 23779564-23785016 0.65 -3.55 PROTEIN
DOWNREG. TU_0013666_0 chr7: 150180552-150189309 0.34 -3.55 PROTEIN
DOWNREG. TU_0036844_0 chr3: 9930878-9933062 0.54 -3.56 PROTEIN
DOWNREG. TU_0014467_0 chr17: 4407802-4410614 0.49 -3.56 NOVEL
DOWNREG. TU_0086397_0 chr14: 104617328-104624500 0.45 -3.56 PROTEIN
DOWNREG. TU_0014721_0 chr17: 6882853-6884238 0.60 -3.57 PROTEIN
DOWNREG. TU_0061867_0 chr1: 41618433-41621890 0.61 -3.57 PROTEIN
DOWNREG. TU_0090901_0 chr11: 20081238-20099725 0.60 -3.57 PROTEIN
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DOWNREG. TU_0024160_0 chr19: 48777171-48778386 0.51 -4.49 PROTEIN
DOWNREG. TU_0031081_0 chrX: 133993992-134013925 0.64 -4.49 PROTEIN
DOWNREG. TU_0015447_0 chr17: 19421649-19423000 0.46 -4.50 PROTEIN
DOWNREG. TU_0016834_0 chr17: 38072130-38072515 0.54 -4.50 PROTEIN
DOWNREG. TU_0120709_0 chr2: 176677352-176697902 0.49 -4.50 PROTEIN
DOWNREG. TU_0041205_0 chr3: 171619688-171634575 0.48 -4.53 PROTEIN
DOWNREG. TU_0110178_0 chr15: 43196270-43241274 0.43 -4.54 PROTEIN
DOWNREG. TU_0084473_0 chr1: 110000292-110079791 0.51 -4.58 ncRNA
DOWNREG. TU_0120715_0 chr2: 176692475-176697902 0.50 -4.58 PROTEIN
DOWNREG. TU_0110180_0 chr15: 43196205-43243358 0.43 -4.63 PROTEIN
DOWNREG. TU_0024922_0 chr19: 54255568-54259943 0.42 -4.64 ncRNA
DOWNREG. TU_0119818_0 chr2: 38109039-38116939 0.32 -4.64 ncRNA
DOWNREG. TU_0067289_0 chr1: 166307141-166318970 0.48 -4.69 NOVEL
DOWNREG. TU_0095765_0 chr11: 117640504-117642734 0.36 -4.69 PROTEIN
DOWNREG. TU_0058445_0 chr1: 9017797-9040122 0.33 -4.70 PROTEIN
DOWNREG. TU_0047068_0 chr4: 23402764-23403824 0.41 -4.72 PROTEIN
DOWNREG. TU_0018882_0 chr17: 38260060-38263683 0.51 -4.82 NOVEL
DOWNREG. TU_0098382_0 chr8: 68494189-68495887 0.23 -4.83 PROTEIN
DOWNREG. TU_0110177_0 chr15: 43196768-43245735 0.47 -4.86 PROTEIN
DOWNREG. TU_0089598_0 chr11: 303980-310982 0.35 -4.87 PROTEIN
DOWNREG. TU_0107527_0 chr22: 37740155-37746215 0.44 -4.88 PROTEIN
DOWNREG. TU_0107528_0 chr22: 37741248-37746215 0.43 -4.90 PROTEIN
DOWNREG. TU_0032311_0 chr14: 23612588-23617134 0.32 -5.04 indicates
data missing or illegible when filed
TABLE-US-00005 TABLE 5 Fold change Expected score Observed (PCA vs
q-value PCAT ID Gene Chromosomal Location (dExp) score (d) Benign
(%) PCAT-1 TU_0099866_0 chr8: 128087842-128095202 -2.2654014
5.444088 6.9071784 0 PCAT-2 TU_0090142_0 chr11: 4745677-4760303
-2.4408573 4.6781354 11.39658 0 PCAT-3 TU_0054605_0 chr16:
82380336-82394836 -2.1786723 4.4612455 5.8916535 0 PCAT-4
TU_0090140_0 chr11: 4748163-4759145 -2.1153826 4.4345 7.1933164 0
PCAT-5 TU_0078286_0 chr12: 2393286-32405731 -1.9164219 4.312603
3.5655262 0 PCAT-6 TU_0090864_0 chr6: 128084589-128103681
-1.7214081 4.265536 3.8937242 0 PCAT-7 TU_0084308_0 chr5:
15938756-15949124 -1.9636476 4.124071 4.747601 0 PCAT-8
TU_0084303_0 chr6: 15899476-15955226 -2.0245786 4.0520086 7.1035067
0 PCAT-9 TU_0082746_0 chr12: 120197102-120197416 -1.861408
3.7551165 5.1431665 0 PCAT-10 TU_0078296_0 chr12: 32394534-32405549
-1.5944241 3.6902914 3.034359 0 PCAT-11 TU_0078290_0 chr12:
32394534-32410898 -1.5337954 3.675318 3.1572607 0 PCAT-12
TU_0002597_0 chr12: 32394534-32410898 -1.6263148 3.6469774 3.352418
0 PCAT-13 TU_0049368_0 chr6: 34335202-34338521 -1.6894234 3.6079373
2.8299546 0 PCAT-14 TU_0106548_0 chr4: 106772318-106772770
-1.939075 3.591398 5.3962547 0 PCAT-15 TU_0078293_0 chr22:
22209111-22212055 -1.5212961 3.5705945 2.9213174 0 PCAT-16
TU_0099834_0 chr8: 128301495-128307576 -1.4445064 3.5658643
2.516981 0 PCAT-17 TU_0112014_0 chr15: 67722165-67739990 -1.6326295
3.562463 3.694224 0 PCAT-18 TU_0084306_0 chr5: 15896315-15947086
-1.845 3.5603588 5.746707 0 PCAT-19 TU_0124240_0 chr2:
1534883-1538193 -1.6870209 3.5233572 4.339847 0 PCAT-20
TU_0008439_0 chr7: 24236191-24236455 -1.6302066 3.5071697 6.6821446
0 PCAT-21 TU_0078299_0 chr12: 32200296-32292169 -1.7297353 3.606232
3.2923664 0 PCAT-22 TU_0000033_0 chr6: 1619606-1668581 -1.7680657
3.434185 2.2470813 0 PCAT-23 TU_0096472_0 chr11:
133844590-133862924 -1.8782617 3.410356 5.9854193 0 PCAT-24
TU_0114259_0 chr2: 1686782-1687314 -1.6662377 3.3919659 5.080926 0
PCAT-25 TU_0096473_0 chr11: 133844500-133862995 -1.8963361 3.859823
6.1071715 0 PCAT-26 TU_0100362_0 chr8: 144914456-144930753
-1.6521469 3.3805158 3.8420231 0 PCAT-27 TU_0040394_0 chr3:
135418632-133441252 -1.6208396 3.3201025 2.8724674 0 PCAT-28
TU_0043432_0 chr13: 34062994-34056503 -1.6739871 3.2037551
3.2093527 0 PCAT-29 TU_0112020_0 chr15: 67764259-67801825
-1.5603316 3.1967351 3.593551 0 PCAT-30 TU_0042717_0 chr13:
23149908-23200198 -1.0654948 3.1685438 4.9633407 0 PCAT-31
TU_0078232_0 chr12: 62290485-62406307 -1.4503008 3.151879 2.8011364
0 PCAT-32 TU_0084146_0 chr5: 14025126-14062770 -1.6452767 3.1257985
2.6193055 0 PCAT-33 TU_0066168_0 chr18: 22477042-22477666
-1.5381516 3.0557241 3.1951044 0 PCAT-34 TU_0040383_0 chr3:
133360941-133429262 -1.5558791 3.0416508 3.7478442 0 PCAT-35
TU_0112025_0 chr15: 67780574-87782345 -1.6815977 3.0412362 3.433415
0 PCAT-36 TU_0041688_0 chr3: 186743298-186741933 -1.4748297
3.0062308 2.543468 0 PCAT-37 TU_0103642_0 chr9: 109187089-109187455
-1.7387192 2.998958 6.6124363 0 PCAT-38 TU_0040375_0 chr3:
133280694-133394609 -1.5469999 2.9753568 3.9068055 0 PCAT-39
TU_0047312_0 chr4: 19217689-39222163 -1.6388936 2.9124916 3.6121209
0 PCAT-40 TU_0106545_0 chr22: 22218478-22219162 -1.7586407 2.889856
3.7357745 0 PCAT-41 TU_0054541_0 chr16: 79408800-79435066
-1.7485934 2.8699164 6.647557 0 PCAT-42 TU_0060446_0 chr1:
28438629-28450156 -1.4880521 2.857332 1.0824111 0 PCAT-43
TU_0072907_0 chr20: 55759486-55771563 -1.5254781 2.7966201 2.812179
0 PCAT-44 TU_0043453_0 chr13: 33844637-33845921 -1.5793877
2.7919009 3.6403422 0 PCAT-45 TU_0038678_0 chr3: 53515951-53517078
-1.7047809 2.7858517 3.6909987 0 PCAT-46 TU_0101786_0 chr9:
3408690-3415374 -1.4780945 2.7822099 3.3066912 0 PCAT-47
TU_0101709_0 chr9: 3411967-3415374 -1.4852373 2.7622206 3.1886175 0
PCAT-48 TU_0166544_0 chr22: 22210421-22220506 -1.6153399 2.7578155
3.7418716 0 PCAT-49 TU_0046121_0 chr4: 766363-766599 -1.5697786
2.7573307 1.485532 0 PCAT-50 TU_0106542_0 chr22: 22211315-22220506
-1.6098742 2.755221 3.3781004 0 PCAT-51 TU_0106541_0 chr22:
22209111-22219162 -1.6593723 2.7341027 3.664146 0 PCAT-52
TU_0044453_0 chr13: 51505777-51524522 -1.3416 2.732019 2.536953 0
PCAT-53 TU_0104717_0 chr9: 130697833-130698832 -1.2938 2.7219732
2.3344588 0 PCAT-54 TU_0039014_0 chr5: 176014905-176015351
-1.3967873 2.7047258 3.7803582 0 PCAT-55 TU_0168452_0 chr15:
19344745-19362916 -1.5839852 2.6759455 1.8484153 0 PCAT-56
TU_0112053_0 chr15: 67645590-67775246 -1.4386703 2.668052 3.045022
0 PCAT-57 TU_0078286_0 chr12: 32395588-32405731 -1.3580605
2.6660874 2.6121044 0 PCAT-58 TU_0078303_0 chr12: 32274210-32274530
-1.5020599 2.65856 3.3306372 0 PCAT-59 TU_0112054_0 chr15:
67644390-67650387 -1.5175762 2.8509888 2.9933636 0 PCAT-60
TU_0071087_0 chr20: 21428679-21429454 -1.4916688 2.649109 4.6481714
0 PCAT-61 TU_0072906_0 chr20: 95759768-55770657 -1.5059631 2.645004
2.95756 0 PCAT-62 TU_0054240_0 chr16: 70155175-70173873 -1.4715649
2.6437716 3.5309577 0 PCAT-63 TU_0047330_0 chr4: 39217641-39222163
-1.5139307 2.6277235 3.0695639 0 PCAT-64 TU_0055435_0 chr18:
6715938-6719172 -1.6048826 2.6173768 2.9221427 0 PCAT-65
TU_0079791_0 chr12: 54971063-54971481 -1.4415668 2.6010823
2.0141602 0 PCAT-66 TU_0043411_0 chr13: 33918267-33926769 -1.495064
2.5991623 3.3860362 0 PCAT-67 TU_0056121_0 chr18: 20196762-20197522
-1.2526748 2.5938754 1.7191441 0 PCAT-68 TU_0043412_0 chr13:
33918267-33935946 -1.5891836 2.5901399 4.2804045 0 PCAT-69
TU_0065837_0 chr1: 149791252-149795934 -1.3852053 2.5882297
2.9343975 0 PCAT-70 TU_0043461_0 chr13: 33825711-33845275
-1.5994886 2.5853698 4.3461533 0 PCAT-71 TU_0006453_0 chr6:
144659813-144660143 -1.4985942 2.5744107 2.2007995 0 PCAT-72
TU_0048596_0 chr4: 30329017-80348259 -1.5744382 2.5690413 2.8022916
0 PCAT-73 TU_0084140_0 chr5: 14003669-14054874 -1.4040573 2.5472755
2.5979325 0 PCAT-74 TU_0082982_0 chr12: 121776584-121777370
-1.5293782 2.5458217 2.6197503 0 PCAT-75 TU_0013212_0 chr7:
13890883-139001515 -1.2298403 2.544434 1.6879753 0 PCAT-76
TU_0072912_0 chr20: 55779532-55780817 -1.4302964 2.5406737
3.2653345 0 PCAT-77 TU_0112281_0 chr15: 70586704-70590792
-1.4590155 2.5875097 2.4288568 0 PCAT-78 TU_0048787_0 chr4:
88120068-88124880 -1.3735119 2.5328946 2.233808 0 PCAT-79
TU_0108455_0 chr15: 19358626-19365341 -1.6651321 2.5261333
1.9462687 0 PCAT-80 TU_0091997_0 chr11: 58560356-58573012
-1.3149038 2.5185204 2.1176686 0 PCAT-81 TU_0122655_0 chr2:
202985284-202998634 -1.4014161 2.476237 2.2194188 0.859614 PCAT-82
TU_0071798_0 chr20: 33775260-33778511 -1.3388665 2.4848917
1.65688733 0.850371 PCAT-83 TU_0049200_0 chr4: 102469973-102476087
-1.3222212 2.456723 1.9456172 0.841324 PCAT-84 TU_0121714_0 chr2:
203295212-203314865 -1.3457565 2.4496663 1.7624274 0.832468 PCAT-85
TU_0098937_0 chr2: 95748751-95751821 -1.4532137 2.42248 2.2326834
0.823797 PCAT-86 TU_0108453_0 chr15: 19356996-19364013 -1.8033699
2.4094539 3.839975 0.767811 PCAT-87 TU_0114170_0 chr15:
99659312-99669199 -1.4358851 2.4062114 2.1252658 0.768711 PCAT-88
TU_0089906_0 chr11: 1042845-1045705 -1.3899238 2.401665 2.839095.5
0.767811 PCAT-89 TU_0001559_0 chr6: 30283700-30286011 -1.3517065
2.3987799 1.5110766 0.767811 PCAT-90 TU_0050557_0 chr4:
159976338-160016453 -1.17525 2.398688 2.0524442 0.767811 PCAT-91
TU_0078294_0 chr12: 32395632-32413084 -1.4560982 2.3969867
2.1863208 0.767811 PCAT-92 TU_0044933_0 chr13: 94755992-94760688
-1.2905197 2.3965187 2.189938 0.767811 PCAT-93 TU_0017730_0 chr17:
52346638-52346880 -1.4169512 2.3874857 1.4708191 0.760428 PCAT-94
TU_0039020_0 chr3: 66578629-66507777 -1.2662895 2.3720088 1.7112708
0.712473 PCAT-95 TU_0049213_0 chr4: 102461960-102476087 -1.2725139
2.3871806 1.8878821 0.712473 PCAT-96 TU_0093070_0 chr11:
64945809-64961189 -1.2954472 2.3645105 1.9128969 0.712473 PCAT-97
TU_0051063_0 chr4: 187244297-187244767 1.8922851 -2.8485844
0.50983155 0.732264 PCAT-98 TU_0098190_0 chr8: 61704765-61708199
1.9825526 -2.8612607 0.4027831 0.732264 PCAT-99 TU_0038811_0 chr3:
57890130-57890884 1.9820296 -2.8837616 0.44431657 0.732264 PCAT-100
TU_0020814_0 chr19: 9718812-9721799 1.8433232 -2.9248087 0.50623006
0.732264 PCAT-101 TU_0112056_0 chr15: 89658838-69678409 1.837821
-3.0355222 0.48161976 0 PCAT-102 TU_0056396_0 chr14:
104617328-104619095 1.549786 -3.1192882 0.45514825 0 PCAT-103
TU_0095765_0 chr11: 117640504-117642734 2.1002219 -3.2632742
0.38160667 0 PCAT-104 TU_0050224_0 chr4: 147115887-147190781
2.1981242 -3.2975357 0.28569755 0 PCAT-105 TU_0112089_0 chr15:
69667695-60691724 1.8148681 -3.3816626 0.43567468 0 PCAT-106
TU_0098382_0 chr8: 68494189-68495887 2.5433978 -4.0586042
0.30793378 0
TABLE-US-00006 TABLE 6 Median Maximum Expression Expression PCAT ID
Gene Chromosomal Location Outlier Score (RPKM) (RPKM) PCAT-107
TU_0029004_0 chrX: 66691350-56692032 130.7343145 1 90.921 PCAT-108
TU_0054542_0 chr16: 79420131-79423590 227.0430857 5.60998 135.85
PCAT-109 TU_0120899_0 chr2: 180689090-180696402 223.5416436
1.0525222 94.6932 PCAT-110 TU_0054540_0 chr16: 79419351-79423673
119.050847 4.161985 94.4461 PCAT-111 TU_0120918_0 chr2:
181297540-181400892 112.710111 1.4533705 92.1795 PCAT-112
TU_0054538_0 chr16: 79408946-79450819 93.01851659 1.830343 93.1207
PCAT-113 TU_0059541_0 chr2: 20685471-20686432 68.3572507 1.783109
1375.15 PCAT-114 TU_0120524_0 chr2: 181331111-181427485 63.95455962
1.3891845 365.202 PCAT-115 TU_0074308_0 chr10: 42652247-42653596
60.91841567 1.393607 65.7712 PCAT-116 TU_0049192_0 chr4:
102257900-102306678 59.24997694 1.3854525 69.2423 PCAT-117
TU_0054537_0 chr16: 79406933-79430041 53.04481877 1.8534395 42.751
PCAT-118 TU_0120900_0 chr2: 180916864-180985957 55.8438747 1
67.6582 PCAT-119 TU_0114527_0 chr2: 10858318-10858530 54.76455104
1.2969775 35.0059 PCAT-120 TU_0120923_0 chr2: 181328093-181419226
52.9783227 1.2821 232.556 PCAT-121 TU_0049231_0 chr4:
102257900-102259695 52.77001947 1.34042 67.6276
TABLE-US-00007 TABLE 7 Median Maximum Outlier Expression Expression
Rank Gene Chromosomal location Score (RPKM) (RPKM) 1 CRISP3 chr6:
49803053-49813070 294.56446 1.5414775 478.812 2 SPINK1 chr5:
147184335-147191453 177.19518 2.484455 624.733 3 TU_0029004_0 chrX:
66691350-66692032 130.73491 1 90.921 4 TU_0054542_0 chr16:
79420131-79423590 127.0431 5.60998 135.85 5 TU_0120899_0 chr2:
180689090-180696402 123.54164 1.0525222 94.6932 6 ERG chr21:
38673821-38792298 119.446 3.421615 178.826 7 TU_0054540_0 chr16:
79419351-79423673 119.09085 4.161985 94.4461 8 ERG chr21:
38673821-38792298 117.60294 3.470755 176.186 9 ERG chr21:
38673821-38955574 117.26408 3.385695 170.663 10 ERG chr21:
38673821-38955574 116.33448 3.40077 170.443 11 TU_0120918_0 chr2:
181297540-181400892 112.71011 1.4533705 92.1795 12 C7orf68 chr7:
127883119-127885708 105.18504 6.835525 336.148 13 CSRP3 chr11:
19160153-19180106 101.12947 1 148.45 14 C7orf68 chr7:
127883119-127885708 100.63202 7.08303 337.76 15 COL2A1 chr12:
46653014-46684552 99.166329 1.2285615 96.0977 16 C1orf64 chr1:
16203317-16205771 98.085922 3.62012 252.013 17 TU_0054538_0 chr16:
79403946-79450819 98.018517 1.830343 93.1207 18 COL2A1 chr12:
46653014-46684552 97.347905 1.2416035 94.6672 19 CSRP3 chr11:
19160153-19180165 96.730187 1 141.963 20 COL9A2 chr1:
40538749-40555526 74.408443 19.24815 570.961 21 PLA2G7 chr6:
46780012-46811389 69.521175 10.83567 97.8331 22 AGT chr1:
228904891-228916959 69.319886 4.797365 189.281 23 TU_0059541_0
chr1: 20685471-20686432 68.357251 1.783109 1375.15 24 ETV1 chr7:
13897382-13992664 68.218569 1.932797 138.519 25 ETV1 chr7:
13897382-13992664 67.723331 1.9899945 142.406 26 ETV1 chr7:
13897382-13992664 67.680571 1.9915925 143.632 27 PLA2G7 chr6:
46780011-46811110 67.089039 10.62 95.3551 28 ETV1 chr7:
13897382-13997390 66.381191 2.097225 143.975 29 ETV1 chr7:
13897382-13997575 65.563724 2.074935 141.069 30 MUC6 chr11:
1002823-1026706 64.7328 1.466194 351.862 31 TU_0120924_0 chr2:
181331111-181427485 63.95456 1.3891845 365.202 32 ETV1 chr7:
13897382-13996167 63.929225 2.05648 135.131 33 ETV1 chr7:
13897382-13996167 62.424072 2.03086 131.644 34 TU_0074308_0 chr10:
42652247-42653596 60.918416 1.393607 65.7712 35 TU_0049192_0 chr4:
102257900-102306678 59.249977 1.3854525 69.2423 36 TU_0054537_0
chr16: 79406933-79430041 58.04482 1.8534395 42.751 37 RGL3 chr19:
11365731-11391018 57.528689 7.660035 91.2238 38 RGL3 chr19:
11365731-11391018 57.393056 7.6327 90.6937 39 TMEM458 chr11:
129190950-129235108 55.887845 4.87695 60.0414 40 TU_0120900_0 chr2:
180926364-180935967 55.843875 1 67.6582 41 PTK6 chr20:
61630219-61639151 55.101291 3.420545 114.116 42 TU_0114527_0 chr2:
10858318-10858530 54.764551 1.2969775 35.0059 43 TU_0112020_0
chr15: 67764259-67801825 53.832769 2.0281615 88.99 44 TU_0120923_0
chr2: 181328093-181419226 52.979323 1.2821 232.556 45 TU_0049231_0
chr4: 102257900-102259695 52.770019 1.34042 67.6276 46 MON1B chr16:
75782336-75791044 51.717027 26.00355 187.807 47 TU_0054541_0 chr16:
79408800-79435066 50.445248 1.7164375 32.5832 48 TU_0087466_0 chr5:
136779809-136798173 50.285169 1.2738505 42.0309 49 DLX1 chr2:
172658453-172662647 50.043039 2.088625 43.0035 50 TU_0108209_0
chr22: 46493579-46531245 47.753833 1.0491419 26.6643 51 DLX1 chr2:
172658453-172662647 47.159314 1.9682735 38.4705 52 SMC4 chr3:
161600123-161635435 47.127047 4.581655 63.2353 53 SMC4 chr3:
161601040-161635435 46.967013 4.442065 61.2756 54 TU_0102399_0
chr9: 35759438-35761676 46.664973 6.44675 179.711 55 TU_0029005_0
chrX: 66690414-66704178 46.155567 1.0870047 38.3022 56 C15orf48
chr15: 43510054-43512939 45.732195 19.02125 223.42 57 C15orf48
chr15: 43510054-43512339 45.549287 21.28355 248.097 58 EFNA3 chr1:
153317971-153326638 44.993943 3.68358 70.5016 59 TU_0043412_0
chr13: 33918267-33935946 44.506741 1.311142 15.1968 60 TU_0069093_0
chr1: 220878648-220886461 42.645673 1.443496 160.898 61 UGT1A6
chr2: 234265059-234346684 42.500058 1.937622 45.753 62 TU_0057051_0
chr18: 54524352-54598419 42.108622 2.418785 56.0712 63 AMH chr19:
2200112-2203072 41.744334 2.16026 91.244 64 TU_0120908_0 chr2:
181147971-181168431 41.650097 1.0750564 48.7957 65 TU_0099873_0
chr8: 128138926-128140075 41.420293 1.51101 38.7353 66 HN1 chr17:
70642938-70662369 40.495209 16.35625 110.208 67 TU_0022570_0 chr19:
20341299-20343938 39.984803 2.912835 98.5739 68 TU_0098937_0 chr8:
95748751-95751321 39.740546 1.4422495 51.5935 69 TU_0040375_0 chr3:
133280694-133394609 39.664781 2.149005 90.9787 70 HN1 chr17:
70642938-70662370 39.655603 16.34725 109.587 71 TU_0120929_0 chr2:
181328093-181423017 39.419483 1.2116475 189.765 72 TU_0112004_0
chr15: 67644390-67650387 39.300923 6.10665 76.723 73 TU_0108439_0
chr15: 19293567-19296333 39.131646 1 27.7534 74 HN1 chr17:
70642938-70662369 39.00893 15.53595 103.782 75 SULT1C2 chr2:
108271526-108292803 39.007062 1.2259165 91.5617 76 STX19 chr3:
95215904-95230144 38.954223 4.521255 46.0375 77 TU_0030420_0 chrX:
112642982-112685485 38.715477 1.0890785 62.9419 78 TU_0099875_0
chr8: 128138047-128140075 38.489447 1.393413 35.8984 79 IJBE2T
chr1: 200567406-200577717 38.387515 3.070345 85.9738 80 SULT1C2
chr2: 108271526-108292803 37.817555 1.215033 88.0858 81
TU_0049429_0 chr4: 109263508-109272353 37.794245 1.09915225 29.1838
82 STMN1 chr1: 26099193-26105955 37.319869 14.3784 187.062 83
UGT1A1 chr2: 234333657-234346684 37.267194 1.660554 35.9476 84
LRRN1 chr3: 3816120-3864387 37.229013 3.8912 137.117 85
TU_0886631_0 chr5: 113806149-113806936 36.896806 1.0501165 29.6561
86 ORM2 chr9: 116131889-116135357 36.878688 3.614505 120.139 87
TU_0084060_0 chr5: 7932238-7932523 36.807599 1 23.1979 88
TU_0098644_0 chr8: 81204784-81207034 36.779294 1.6013735 64.9663 89
ACSM1 chr16: 20542059-20610079 36.280896 13.3707 317.077 90 STMN1
chr1: 26099193-26105231 35.882914 12.73275 164.721 91 STMN1 chr1:
26099193-26105580 35.823453 14.31935 185.329 92 TU_0120914_0 chr2:
181265370-181266053 35.551458 1.053468 30.7074 93 UGT1A7 chr2:
234255322-234346684 35.073998 1.667349 33.4378 94 TU_0087462_0
chr5: 136386339-136403134 34.992335 1.4450115 27.1703 95 UGT1A3
chr2: 234302511-234346684 34.952247 1.6889365 33.4202 96 UGT1A5
chr2: 234286376-234346684 34.950003 1.6639345 33.2718 97 FOXD1
chr5: 72777840-72780108 34.875512 1.2373575 10.80944 98 ADM chr11:
10283217-10285499 34.855767 11.83635 276.194 99 PPFIA4 chr1:
201286933-201314487 34.769924 1.566044 43.9812 100 UGT1A10 chr2:
234209861-234346690 34.738527 1.652799 32.7318 101 UGT1A4 chr2:
234292176-234346684 34.663597 1.655824 32.9264 102 UGT1A9 chr2:
234245282-234346690 34.648086 1.655272 32.852 103 TU_0090142_0
chr11: 4748677-4760303 34.517072 1.6226305 51.3411 104 TU_0082746_0
chr12: 120197102-120197416 34.499713 2.531095 59.9026 105 UGT1A8
chr2: 234191029-234346684 34.433379 1.6498025 32.5849 106
TU_0112207_0 chr15: 70278422-70286121 34.308752 10.40266 112.274
107 LOC145837 chr15: 67641112-67650833 34.291574 7.59729 74.8194
108 TU_0050712_0 chr4: 170217424-170228463 34.23107 1.504313
65.5606 109 TU_0043410_0 chr13: 33929484-33944669 34.112491
1.393529 24.8401 110 SNHG1 chr11: 62376035-62379936 33.971989
33.74365 270.512 111 MUC1 chr1: 153424923-153429324 33.838228
16.3238 664.278 112 MUC1 chr1: 153424923-153429324 33.828147
15.8436 644.44 113 TU_0099871_0 chr8: 128138047-128143500 33.697285
1.412872 33.2958 114 TU_0040383_0 chr3: 133360541-133429262
33.548813 2.553955 85.8384 115 MUC1 chr1: 153424923-153429324
33.495501 15.91355 627.622 116 TU_0049202_0 chr4:
102257900-102304755 33.391066 1.5555505 39.7522 117 TU_0120913_0
chr2: 181254530-181266950 33.188328 1 43.8515 118 B4GALNT4 chr11:
359794-372116 33.176248 6.3749 80.9639 119 TU_0100059_0 chr8:
141258835-141260573 33.169029 1.3615865 44.8943 120 TOP2A chr17:
35798321-35827695 33.132056 1.9725825 34.1032 121 MUC1 chr1:
153424923-153429324 33.081326 15.9539 632.042 122 TU_0001265_0
chr6: 27081719-27082291 33.045746 1.3381905 100.5401 123 C7orf53
chr7: 111908143-111918171 33.024251 2.820945 32.2465 124 SLC45A2
chr5: 33980477-34020537 32.952911 2.012104 54.8589 125 TU_0099869_0
chr8: 128138047-128225937 32.928048 1.308804 30.4657 126 UGT1A6
chr2: 234266250-234346690 32.918772 1.662221 31.4671 127
TU_0120917_0 chr2: 181265370-181266950 32.796137 1.0771403 36.3557
128 CACNA1D chr3: 53504070-53821532 32.608994 4.51306 44.9904 129
UBE2C chr20: 43874661-43879003 32.456813 1.6391285 58.398 130 ALDOC
chr17: 23924259-23928078 32.455953 14.98415 228.812 131 MUC1 chr1:
153424923-153429324 32.44845 15.5895 599.062 132 MMP11 chr22:
22445035-22456503 32.411555 3.257735 73.9158 133 TU_0084303_0
chr5:15899476-15955226 32.39036 2.21168 14.4385 134 CACNA1D chr3:
53504070-53821532 32.381439 4.484655 44.6867 135 UBE2C chr20:
43874661-43879003 32.358151 1.705223 57.8559 136 CACNA1D chr3:
53504070-53821532 32.353332 4.463805 44.2455 137 FGFRL1 chr4:
995609-1010686 32.275762 26.0133 450.449 138 FGFRL1 chr4:
996251-1010686 32.075261 27.0148 468.809 139 FGFRL1 chr4:
995759-1010686 32.069901 26.92945 457.246 140 MUC1 chr1:
153424923-153429324 32.011017 15.3218 586.058 141 TU_0099922_0
chr8: 128979617-128981414 31.833339 3.32544 32.6893 142
TU_0001173_0 chr6: 26385234-26386052 31.823293 2.339595 71.3388 143
MUC1 chr1: 153424923-153429324 31.781267 15.22945 587.582 144
TMEM178 chr2: 39746141-39798605 31.614406 13.40605 182.08 145 UBE2C
chr20: 43874661-43879003 31.37539 1.7154185 58.1531 146 KCNC2
chr12: 73720162-73889778 31.294059 1.8783795 104.225 147 MAGEC2
chrX: 141117794-141120742 31.286618 1 34.1099 148 SERHL2 chr22:
41279868-41300332 31.131788 3.670135 61.9969 149 KCNC2 chr12:
7.3720162-73889778 31.126593 1.868714 108.199 150 GRAMD4 chr22:
45401321-45454352 31.063732 5.977725 79.8338
[0383] Table 8 shows the number of cancer-associated lncRNAs
nominated for four major cancer types. The number validated is
indicated in the column on the right. This table reflects ongoing
efforts.
TABLE-US-00008 TABLE 8 # of cancer-specific in cRNAs nominated #
validated to date Prostate cancer 121 11 Breast cancer 6 6 Lung
cancer 36 32 Pancreatic cancer 34 0
Example 2
SchLAP-1 ncRNA
Methods
Cell Lines
[0384] All cell lines were obtained from the American Type Culture
Collection (Manassas, Va.). Cell lines were maintained using
standard media and conditions. SChLAP-1 or control expressing cell
lines were generated by cloning SChLAP-1 or control into the
pLenti6 vector (Invitrogen). Stably-transfected RWPE, HME and MCF7
cells were selected using blasticidin (Invitrogen). For LNCAP and
22Rv1 cells with stable knockdown of SChLAP-1, cells were
transfected with SChLAP-1 or non-targeting shRNA lentiviral
constructs for 48 hours. GFP+ cells were drug-selected using
puromycin.
RNA Isolation; cDNA Synthesis; and PCR Experiments
[0385] RNA isolation and cDNA synthesis was performed according
standard protocols. Quantitative PCR was performed using Power SYBR
Green Mastermix (Applied Biosystems, Foster City, Calif.), using
GAPDH and HMBS as housekeeping control genes. The relative quantity
of the target gene was completed for each sample using the
.DELTA..DELTA.Ct method.
Murine Intracardiac and Subcutaneous In Vivo Models
[0386] Intracardiac injection model: 5.times.10.sup.5 cells were
introduced to CB-17 severe combine immunodeficient mice (CB-17
SCID) at 6 weeks of age. Beginning one week post injection,
bioluminescent imaging of mice was performed weekly using a CCD
IVIS system with a 50-mm lens (Xenogen Corp.) and the results were
analyzed using LivingImage software (Xenogen). Subcutaneous
injection model: 1.times.10.sup.6 cells were introduced to mice
(CB-17 SCID), ages 5-7 weeks, with a matrigel scaffold (BD Matrigel
Matrix, BD Biosciences) in the posterior dorsal flank region (n=10
per cell line). Tumors were measured weekly using a digital
caliper, and endpoint was determined as a tumor volume of 1000
mm.sup.3.
Immunoblot Analysis
[0387] Cells were lysed in RIPA lysis buffer (Sigma, St. Louis,
Mo.) supplemented with HALT protease inhibitor (Fisher). Western
blotting analysis was performed with standard protocols using
Polyvinylidene Difluoride membrane (GE Healthcare, Piscataway,
N.J.) and the signals visualized by enhanced chemiluminescence
system as described by the manufacturer (GE Healthcare).
siRNA Knockdown, Proliferation and Invasion Studies
[0388] Cells were plated in 100 mM plates at a desired
concentration and transfected with 20 uM experimental siRNA oligos
or non-targeting controls according to standard protocols. 72 hours
post-transfection with siRNA, cells were trypsinized, counted with
a Coulter counter, and diluted to 1 million cells/mL. Proliferation
assays were performed with a Coulter counter, and invasion of cells
through Matrigel (BD Biosciences) was performed according to
standard protocols
RNA Immunoprecipitation
[0389] RIP assays were performed using a Millipore EZ-Magna RIP
RNA-Binding Protein Immunoprecipitation kit (Millipore, #17-701)
according to the manufacturer's instructions.
Mayo Clinic Cohort Analyses
[0390] Formalin-fixed paraffin embedded (FFPE) samples from 235
prostate cancer patients from the Mayo Clinic43 were processed for
total RNA using the RNeasy FFPE nucleic acid extraction kit
(Qiagen). RNA was subjected to whole-transcriptome amplification
using the WT-Ovation FFPE system (NuGen, San Carlos, Calif.),
biotin-labelled with the Encore Biotin Module (NuGen), and
hybridized to Affymetrix Human Exon (HuEx) 1.0 ST GeneChips
(Affymetrix, Santa Clara Calif.). Microarray data was analyzed as
detailed previously (Vergara et al. Front Genet. 3, 23, (2012), and
SChLAP-1 expression was determined by Partition Around Medoids
(PAM) unsupervised clustering using probe selection region
2518129.
Statistical Analyses for Experimental Studies
[0391] All data are presented as means.+-.S.E.M. All experimental
assays were performed in duplicate or triplicate. Statistical
analyses shown in figures represent Fisher's exact tests or
two-tailed Student t-tests, as indicated.
Results
[0392] RNA-Seq has been used to profile >100 prostate cell lines
and tissues, including both localized and metastatic prostate
cancers (Prensner, et al. Nat Biotechnol 29, 742-749, (2011)).
Given that only a fraction of prostate cancers present with
aggressive clinical features (Cooperberg et al., J Clin Oncol 23,
8146-8151 (2005)), cancer outlier profile analysis (COPA; Tomlins
et al., Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS
transcription factor Tomlins et al., Science 310, 644-648, science
310 644-648 (2005)) was performed to nominate intergenic lncRNAs
selectively upregulated in a subset of cancers. PCAT-109 and
PCAT-114 showed striking outlier profiles and ranked among the best
outliers in prostate cancer when compared to protein-coding genes
(FIG. 40a). Notably, both are located in a "gene desert" on
Chromosome 2q31.3, a region with previously unknown ties to
prostate cancer (FIG. 40b and FIG. 43).
[0393] Efforts to validate PCAT-109 by PCR and rapid amplification
of cDNA ends (RACE) failed, partly due to the fact that this gene
is not robustly expressed in any prostate cell lines (FIG. 40b and
data not shown). By contrast, in the PCAT-114 region, PCR
experiments and 5' and 3' RACE defined a 1.4 kb, poly-adenylated
gene composed of up to seven exons and spanning nearly 200 kb on
Ch2q31.3 (FIG. 40c and FIG. 44). This gene was named Second
Chromosome Locus Associated with Prostate-1 (SChLAP-1) after its
genomic location. To further characterize this gene, a published
ChIP-Seq dataset of prostate cancer (Yu et al. Cancer Cell 17,
443-454 (2010)) was used and it was found that the transcriptional
start site (TSS) of SChLAP-1 was marked by tri-methylation of H3K4
(H3K4me3) and its gene body harbored tri-methylation of H3K36
(H3K36me3) (FIG. 40c), an epigenetic signature consistent with
canonical protein-coding genes and lncRNAs (Guttman et al., Nature
458, 223-227 (2009)). PCR assays defined numerous splicing isoforms
of this gene of which three (termed isoforms #1, #2, and #3,
respectively) constituted the vast majority (>90%) of
transcripts in the cell (FIG. 40d).
[0394] Using quantitative PCR (qPCR), it was validated that
SChLAP-1 was highly expressed in .about.20% of prostate cancers,
including metastatic prostate cancer (FIG. 40e). Moreover,
examination of SChLAP-1 expression in an RNA-seq compendium of
>600 samples, representing >30 tissue types, demonstrated
that SChLAP-1 expression was relatively absent in other tumor types
(FIG. 4), demonstrating prostate cancer specific activity. To
establish SChLAP-1 as a non-coding gene, three isoforms (isoforms
1, 2 and 3) were cloned and in vitro translation assays were
performed, which were negative. It was also found that SChLAP-1
expression in prostate cell lines was predominantly located in the
nucleus (FIG. 400, while most protein-coding mRNAs are located in
the cytoplasm, where they engage the ribosomal translation
machinery.
[0395] To elucidate the functional role for SChLAP-1 in prostate
cancer, siRNA knockdowns of this gene was performed using two
independent siRNAs as well as siRNA to EZH2, which is essential for
cancer cell invasion (Kleer, et al. Proc Natl Acad Sci USA 100,
11606-11611, (2003); Varambally, S. et al. Nature 419, 624-629,
(2002)) as a positive control. In three prostate cancer cell lines
but not breast and lung cancer cells, knockdown of SChLAP-1
dramatically impaired cell invasion in vitro at a level comparable
to EZH2 (FIG. 41a). SChLAP-1 knockdown also impaired cell
proliferation in prostate cells but not nonprostate cells. To
confirm this phenotype, the three most abundant SChLAP-1 isoforms
were overexpressed in RWPE benign immortalized prostate cells at
physiologic levels similar to the LNCaP cell line. While SChLAP-1
overexpression did not impact cell proliferation, RWPE cells
expressing all three SChLAP-1 isoforms, but not control cells,
exhibited the ability to invade through Matrigel model basement
membrane matrix in vitro (FIG. 41b). Overexpression of SChLAP-1 in
HME benign breast or MCF7 breast cancer cells did not induce cell
invasion, consistent with its prostate-specific expression pattern.
These data support a lineage-specific role for SChLAP-1.
[0396] To characterize specific regions of SChLAP-1 essential for
its function, deletion constructs tiling every 250 bp were
overexpressed in RWPE cells. Deletion of a single 250 bp region (bp
1001-1250 for SChLAP-1 isoform #1) shared by all three major
isoforms abrogated SChLAP-1 mediated invasion in RWPE (FIG. 41c).
In silico modeling with RNAfold22 of the SChLAP-1 RNA structure
indicated the presence of a RNA hairpin in this region that is lost
specifically in deletion construct #5 (FIG. 41d), implicating this
secondary structure in the function of the molecule.
[0397] Xenograft analysis of 22Rv1 cells stably knocking down
SChLAP-1 further confirmed that this gene is necessary for
appropriate cancer cell metastatic seeding in vivo. To test this,
intracardiac injection of tumor cells was performed and luciferase
signal from mouse lungs and distant metastases was monitored. These
experiments showed that 22Rv1 shSChLAP-1 cells displayed impaired
metastatic seeding at both proximal (lungs) and distal sites (FIG.
41e). 22Rv1 shSChLAP-1 cells displayed both fewer gross metastatic
sites overall (an average 3.66 metastatic sites in shNT mice vs.
2.07 metastatic sites in shSChLAP-1 #1 and 1.07 sites in shSChLAP-1
#2 mice, p<0.05, Student's t-test) as well as smaller metastatic
tumors when they did form (FIG. 41f). shSChLAP-1 subcutaneous
xenografts displayed slower tumor progression in vivo, though this
was due to delayed tumor engraftment rather than altered tumor
growth kinetics. Together, these in vitro and in vivo data support
a prostate-specific role for SChLAP-1 in cancer cell invasion,
metastasis, and aggressiveness.
[0398] To interrogate SChLAP-1 function, microarray profiling of
22Rv1 and LNCaP prostate cancer cells treated with SChLAP-1 or
control siRNAs was performed, which revealed 165 upregulated and
264 downregulated genes in a highly significant manner (q-value
<0.001), indicating that SChLAP-1 contributes to the positive
and negative regulation of numerous genes.
[0399] After ranking genes according to differential expression by
Significance Analysis of Microarrays (SAM) (Tusher et al., Proc
Natl Acad Sci USA 98, 5116-5121, (2001)), Proc Natl Acad Sci USA
102, 15545-15550 (2005)) was used to search for enrichment across
the Molecular Signatures Database (MSigDB) (Liberzon, A. et al.
Bioinformatics 27, 1739-1740, (2011)). Among the highest ranked
concepts genes positively or negatively correlated with BRM, an
enzymatic subunit of the SWI/SNF chromatin remodeling complex
(Roberts et al., Nat Rev Cancer 4, 133-142 (2004)) were observed
(FIG. 42a, left). This gene set was generated through an analysis
of the SWI/SNF complex in human prostate cancer samples (Shen, H.
et al. Cancer Res 68, 10154-10162, (2008)), making it an attractive
biological insight due to the tissue-specific functions of this
complex. This analysis was mirrored by generating gene signatures
positive and negatively correlated to BRM in the RNA-Seq dataset
and the enrichment for SChLAP-1-regulated genes was confirmed (FIG.
42a, right). SChLAP-1-regulated genes were inversely correlated
with both BRM datasets (FIG. 42a). These results demonstrate that
SChLAP-1 and SWI/SNF regulate gene transcription in opposing
manners, leading to an antagonism of SWI/SNF activity by
SChLAP-1.
[0400] The SWI/SNF complex operates as a large, multi-protein
system that utilizes ATPase enzymatic activity to physically move
nucleosomes and, in doing so, regulates gene transcription
(Roberts, C. W. & Orkin, S. H. Nat Rev Cancer 4, 133-142,
(2004)). Several SWI/SNF complex members are the target of
recurrent, inactivating mutations in cancer, including ARID1A
(Wiegand, K. C. et al. N Engl J Med 363, 1532-1543, (2010); Jones,
S. et al. Science 330, 228-231 (2010)), PBRM1 (Varela, I. et al.
Nature 469, 539-542 (2011)), and SNF5 (Versteege, I. et al. Nature
394, 203-206, (1998)), and numerous studies demonstrate that loss
of SWI/SNF functionality promotes cancer Progression (Robers et
al., supra; Reisman, D., Glaros, S. & Thompson, E. A. Oncogene
28, 1653-1668, (2009)). While SWI/SNF mutations are not commonly
observed in prostate cancer, several reports indicate that
down-regulation of SWI/SNF complex members, particularly BRM,
characterizes some subsets of prostate cancer (Sun, A. et al.
Prostate 67, 203-213, (2007); Shen, H. et al. Cancer Res 68,
10154-10162, (2008)), and mice with a prostate-specific BRM
deletion exhibit prostatic hyperplasia and castration-resistant
cellular proliferation (Shen et al., supra). Thus, antagonism of
SWI/SNF activity by SChLAP-1 is consistent with the oncogenic
behavior of SChLAP-1 and the tumor suppressive behavior of the
SWI-SNF complex.
[0401] To test whether SChLAP-1 antagonizes SWI/SNF-mediated gene
expression regulation, siRNA knockdown of three key components of
the SWI-SNF complex: BRM (also known as SMARCA2), BRG1 (also known
as SMARCA4), and SNF5 (also known as SMARCB1) was performed. Like
BRM, BRG1 serves as an enzymatic subunit of SWI/SNF complex
activity, and SNF5 is an essential subunit thought to bind histone
proteins (Dechassa, M. L. et al. Mol Cell Biol 28, 6010-6021,
(2008)). Knockdown of BRM, BRG1, and SNF5 in two prostate cell
lines, 22Rv1 and LNCaP, followed by expression microarray profiling
generated highly overlapping sets of up- and down-regulated genes,
demonstrating that these factors have broad commonalities in their
function in prostate cells. Knockdown of BRM, BRG1 and SNF5 also
increased the invasiveness and proliferation rate of 22Rv1 cells,
consistent with the role of SWI/SNF in tumor suppression.
Comparison of genes commonly regulated by knockdown of all SWI/SNF
proteins (BRM, BRG1, and SNF5) to genes regulated by SChLAP1
demonstrated an antagonistic relationship where SChLAP1 knockdown
affected the same genes as SWI/SNF but in the opposing direction
(FIG. 42b). These microarray data were used to generate gene
signatures for up- and down-regulated genes upon knockdown of each
SWI/SNF protein (BRM, BRG1, and SNF5) and SChLAP-1. The
significance of the overlap was quantitated using GSEA. Performing
this analysis across two cell lines (22Rv1 and LNCaP) showed that
SWI/SNF and SChLAP-1 affect gene expression in a highly significant
and opposing manner in 23 of 24 total GSEA comparisons (FDR
<0.05) (FIG. 42c). Together, these data demonstrate that
SChLAP-1 functions to modulate SWI/SNF complex activity in prostate
cancer.
[0402] To examine the mechanism of SChLAP-1 regulation of the
SWI/SNF complex, it was examined whether SChLAP-1 regulated SWI/SNF
complex genes themselves. Using Western blots, no change in BRM,
BRG1, or SNF5 protein abundance following SChLAP-1 knockdown or
overexpression was detected, demonstrating that SChLAP-1 regulates
SWI/SNF activity post-translationally. Motivated by reports of
lncRNAs coordinating the function of epigenetic complexes through
direct RNA-protein binding, RNA immunoprecipitation assays (RIP)
were performed for SNF5, a core subunit essential for both BRG1 and
BRM function, in 22Rv1 and LNCaP cells. It was found that
endogenous SChLAP-1, but not other prostate-specific lncRNAs such
as PCA3 and PCAT-1, robustly bound SNF5 protein (FIG. 42d). RIP for
androgen receptor (AR) and SNRNP70, which specifically binds to the
U1 snRNP, served as additional negative controls for these
experiments (FIG. 42d).
[0403] The role of SChLAP-1-SWI/SNF interactions in the functional
role of SChLAP-1 in inducing cell invasion was tested by evaluating
SChLAP-1-SNF5 binding in the RWPE-SChLAP-1 overexpression model,
including overexpression of SChLAP-1 deletion construct #5, which
failed to induce cell invasion (FIG. 41c). Overexpression of both
SChLAP-1 isoform #1 and isoform #2 robustly bound to SNF5, whereas
deletion construct 5 (which lacks bps 1001-1250 in SChLAP-1 isoform
#1) failed to bind SNF5 (FIG. 42e). As controls, AK093002 and
LOC145837, two lncRNAs upregulated in subsets of prostate cancer
that are endogenously expressed in RWPE were measured. Control RIP
experiments for SNRNP70 demonstrated uniformly strong binding of
this protein to U1 in all RWPE cell lines evaluated. Thus, SChLAP-1
regulates SWI/SNF complex activity by directly binding to SWI/SNF
proteins through an interaction dependent on base pairs 1001-1250
of the RNA.
[0404] To explore a potential link between SChLAP-1 and aggressive
prostate cancer associations between SChLAP-1 and gene expression
phenotypes curated from published microarray profiling data were
explored. Given that SChLAP-1 is currently not measured by
microarray platforms, a signature of genes with expression
significantly correlated or anti-correlated to SChLAP-1 expression
in localized tumors was designed and used as a surrogate for
SChLAP-1 expression level. The SChLAP-1 signature was examined
using Oncomine concept analysis (Rhodes, D. R. et al. Neoplasia 9,
166-180 (2007)) and network representations of the significantly
enriched concepts (p-value <1e-6, odds ratio >3.0) were
generated. The networks revealed an association with concepts
related to prostate cancer progression (FIG. 43a). Genes positively
correlated with SChLAP-1 were over-expressed in metastatic and
high-grade localized tumors. Conversely, genes negatively
correlated with SChLAP-1 were under-expressed in metastatic and
high-grade localized tumors.
[0405] The analysis was expanded to include four known cancer
genes: EZH2, a known metastasis gene (Kleer, C. G. et al. Proc Natl
Acad Sci USA 100; 11606-11611, (2003); Varambally, S. et al. Nature
419, 624-629, (2002)) PCA3, a lncRNA biomarker over-expressed in
prostate cancer and used in prostate cancer diagnosis (de Kok, J.
B. et al. Cancer Res 62, 2695-2698 (2002); Tomlins, S. A. et al.
Sci Transl Med 3, 94ra72, (2011)), AMACR, a tissue biomarker of
prostate cancer (Rubin et al., JAMA 287, 1662-1670 (2002)), and
BRM, a SWI/SNF enzymatic subunit under-expressed in advanced
prostate cancer (Shen et al., supra). Control genes were also
analyzed: the nucleoporin genes NUP133 and NUP155, as well as
B-actin (ACTB). The expression profiles of each of these seven
genes was used to derive correlated and anti-correlated gene sets
in the same manner as for SChLAP-1.
[0406] The statistical association between each dataset in the
clinical concept compendium was analyzed with the gene signatures
derived from correlation analysis, including signatures from the
RNA-Seq cohort delineating localized cancer vs. benign tissues,
high grade localized prostate cancer (Gleason .gtoreq.8 vs. Gleason
6), and metastatic vs. primary tumors. Odds ratios, p-values, and
q-values were calculated for each comparison (one-sided Fisher's
exact test). A heat-map visualization of statistically significant
comparisons (q-value <0.01) confirmed a strong association of
SChLAP-1-correlated genes with high-grade and metastatic cancers as
well as poor clinical outcomes (FIG. 43b). In this respect,
SChLAP-1 was highly similar to EZH2, the positive control, which is
widely associated with aggressive, lethal prostate cancer, whereas
PCA3 and AMACR, two biomarkers not associated with disease
progression, strongly associated with Cancer vs. Normal concepts
but not concepts associated with aggressive disease. Kaplan-Meier
analysis of publicly-available datasets for biochemical recurrence
(Glinsky et al., J Clin Invest 113, 913-923, (2004)) and overall
survival (Setlur, S. R. et al. J Natl Cancer Inst 100, 815-825,
(2008)) similarly showed significant associations (log rank test,
p<0.01) between the SChLAP-1 signature and more rapid disease
recurrence and decreased survival probability.
[0407] In order to link SChLAP-1 expression with clinical outcomes
directly, Affymetrix exon microarrays, which harbor probes mapping
to SChLAP-1 exons was used to profile its expression in a
prospectively-designed study of 235 high-risk prostate cancer
patients who underwent radical prostatectomy between 2000-2006 at
the Mayo Clinic (Buerki, C. et al. ASCO Annual Meeting, Abstract
#4565 (2012). Nakagawa, T. et al. PLoS One 3, e2318, (2008)).
Unsupervised clustering was used to define patients into low and
high SChLAP-1 expression groups and the prognostic utility of
SChLAP-1 was evaluated with three clinical endpoints: biochemical
recurrence (BCR), clinical progression to systemic disease (CP),
and prostate cancer-specific mortality (PCSM). At the time of this
analysis, patients had a median follow-up of 8.1 years.
[0408] Kaplan-Meier analyses show SChLAP-1 as a powerful
single-gene predictor of aggressive prostate cancer (FIG. 43c-e).
SChLAP-1 expression was highly significant when distinguishing CP
and PCSM (p=0.00005 and p=0.002, respectively); patients with high
SChLAP-1 expression had 5-year CP- and PCSM-free survival of only
65% and 85%, respectively, compared to 85% and 95% for patients
with low SChLAP-1 expression (FIGS. 43d and 43e). For the BCR
endpoint, high SChLAP-1 expression in patient primary tumor
specimens was associated with a rapid median time-to-progression
(1.9 vs 5.5 years for SChLAP-1 high and low patients, respectively)
(FIG. 43c). These data demonstrate that SChLAP-1 expression retains
its prognostic utility for defining a subgroup of patients more
likely to experience BCR, CP, and PCSM even in high-risk patients,
where most individuals experienced disease recurrence within ten
years post-prostatectomy (FIG. 43c). To independently validate
these findings, the prognostic value of SChLAP-1 for BCR was
assessed using qPCR on a University of Michigan cohort and
confirmed that SChLAP-1 positive patients are at markedly higher
risk for BCR.
[0409] Multivariable and univariable regression analyses of the
Mayo Clinic data demonstrated that SChLAP-1 expression is an
independent predictor of prostate cancer aggressiveness with highly
significant hazard ratios for predicting BCR, CP, and PCSM (HR or
3.045, 0.563, and 4.339, respectively, p<0.01) which were
comparable to other clinical factors such as Gleason score and
advanced clinical stage. Finally, receiver-operator curves (ROC)
demonstrated the discriminative ability of SChLAP-1 expression in
the Mayo Clinic dataset with area-under-the-curve (AUC) values of
0.63, 0.65, and 0.74 for the 5-year prediction of BCR, CP, and
PCSM, which were either equivalent to, or slightly higher than, the
AUC values for Gleason score (0.59, 0.65, and 0.71,
respectively).
[0410] Thus, these data demonstrate that SChLAP-1 expression either
out-performs, or is comparable to, standard clinical parameters
such as clinical stage, lymph node invasion, pre-operative serum
PSA, surgical margin status (SMS) and Gleason score for the
prediction of CP, PCSM, and BCR. The particularly strong prognostic
value of SChLAP-1 expression for CP and PCSM is important, as it is
known that patients who develop BCR do not necessarily progress
further to lethal or clinically significant recurrent disease: that
is, many patients who experience BCR nevertheless die with prostate
cancer but not from it (Simmons et al., Eur Urol 51, 1175-1184,
(2007); Boorjian, S. A. et al. Eur Urol 59, 893-899, (2011)). As
such, CP and PCSM represent more stringent criteria to define
aggressive prostate cancer. Taken together, the findings indicate
that measurement of SChLAP-1 expression in the early development of
prostate cancer serves as a valuable biomarker to stratify patient
outcomes.
[0411] To explore this, SChLAP-1 expression was measured in urine
sediment RNA from 111 biopsy-confirmed prostate cancer patients
with Gleason score. These RNA samples were collected at the time of
PSA screening as described previously (Tomlins, S. A. et al. Sci
Transl Med 3, 94ra72, (2011)). It was found that SChLAP-1 was
significantly higher in Gleason 7 patients vs. Gleason 6 patients
(Welch's Two Sample t-test, p=0.01498). These data support the
utility of SChLAP-1 as a prognostic screening biomarker for
aggressive prostate cancer (Prensner et al., Sci Transl Med 4,
127rv123, (2012)).
[0412] In conclusion, this example describes a lineage-specific
lncRNA that is highly expressed in 15-30% of prostate cancers but
not other tissue or cancer types. In the tissue sets, the
sensitivity ranges from 20-35% and the specificity ranges from
94-100%. SChLAP-1 is highly expressed in a subset of cancers and is
thus a highly specific marker for those cancers. SChLAP-1 directly
binds a core subunit in the SWI/SNF complex, leading to reversion
of SWI/SNF mediated gene expression (FIG. 44f). In model systems,
SChLAP-1 coordinates prostate cancer cell invasion in vitro and
metastatic spread in vivo, and in patient tissue samples SChLAP-1
expression characterizes a metastatic-like gene expression profile
associated with high-grade localized prostate cancers and poor
clinical outcomes. It was further demonstrated that patients with
high SChLAP-1 expression are at markedly increased risk for
developing metastatic and lethal prostate cancer.
[0413] Table 9 shows genes correlated with SChLAP-1.
TABLE-US-00009 TABLE 9 locus nearest_ref_id r p qval chr12:
57180908-57181574 HSD17B6 -0.546164551 0.001483863 0.063564631
chr10: 100995269-100995619 HPSE2 -0.529744166 0 0 chr9:
4585311-4587469 SLC1A1 -0.528631581 0 0 chr12: 104234726-104234975
NT5DC3 -0.52574655 0 0 chr1: 85358698-85358896 LPAR3 -0.519067947 0
0 chr7: 12692212-12693228 SCIN -0.513485431 0 0 chr1:
204328821-204329044 PLEKHA6 -0.512422441 0 0 chr22:
31674282-31676066 LIMK2 -0.50924733 0 0 chr16: 85121881-85127826
KIAA0513 -0.506320229 0 0 chr11: 126310080-126310239 ST3GAL4
-0.506170919 0 0 chr2: 102855651-102856462 IL1RL2 -0.499389029 0 0
chr2: 100759172-100759201 AFF3 -0.498848742 0 0 chr3:
87039767-87040269 VGLL3 -0.4955607 0.001996514 0.07433842 chr10:
106058885-106059616 GSTO2 -0.481459111 0 0 chr18: 78005159-78005429
PARD6G -0.480259815 0.001816685 0.07142087 chr5: 14692962-14699820
FAM105B -0.478056706 0.001989958 0.07433842 chr11:
124955849-124959131 SLC37A2 -0.477004111 0 0 chr11:
134134801-134135749 ACAD8 -0.474921728 0 0 chr12:
104159806-104160505 STAB2 -0.474825465 0 0 chr13: 24462816-24463558
MIPEP -0.47377468 0.000330132 0.017740189 chr15: 89738457-89745591
ABHD2 -0.473687887 0.001901732 0.07290082 chr16: 22295207-22297954
EEF2K -0.471488569 0 0 chr6: 159185526-159185908 SYTL3 -0.470902458
0 0 chr2: 204399833-204400133 RAPH1 -0.469048813 0 0 chr21:
35987058-35987441 RCAN1 -0.468923289 0 0 chr2: 242089022-242089679
PASK -0.468525633 0 0 chr1: 153603987-153604513 S100A1 -0.467663305
0 0 chr9: 77502739-77503010 TRPM6 -0.466199058 0 0 chr5:
66458974-66465423 MAST4 -0.464838512 0 0 chr12: 112247346-112247782
ALDH2 -0.464258794 0 0 chr20: 33460449-33460663 GGT7 -0.464248542 0
0 chr16: 84695183-84701292 KLHL36 -0.462458945 0.001623427
0.067166971 chr5: 55218223-55218678 IL31RA -0.462369779 0 0 chrX:
63615219-63615333 MTMR8 -0.462171273 0 0 chr16: 84538206-84538296
KIAA1609 -0.461782241 0 0 chrX: 18671551-18671749 CDKL5
-0.461589982 0 0 chr10: 94050682-94050844 CPEB3 -0.461125435 0 0
chr18: 11908199-11908779 MPPE1 -0.460707259 0 0 chr3:
189839991-189840226 LEPREL1 -0.459922767 0.002264726 0.074896868
chr1: 154321315-154323783 ATP8B2 -0.459778607 0 0 chr4:
100009839-100009952 ADH5 -0.459096821 0 0 chr2: 202028557-202029033
CFLAR -0.454603271 0 0 chr11: 130272233-130273133 RP11-
-0.453760945 0 0 121M22.1 chr4: 106924870-106925184 NPNT
-0.453089747 0.001896636 0.07290082 chr17: 53809031-53809482
TMEM100 -0.452269788 0 0 chr18: 19102618-19102791 GREB1L
-0.45014015 0 0 chr7: 128461852-128462186 CCDC136 -0.449966828 0 0
chr4: 113206795-113207059 TIFA -0.44794294 0 0 chr13:
111955337-111958084 ARHGEF7 -0.447155527 0 0 chr7:
103086544-103086624 SLC26A5 -0.446130747 0.001571059 0.065901041
chr2: 199436579-199437305 PLCL1 -0.445732252 0 0 chr7:
99526462-99527243 GJC3 -0.44536614 0 0 chr17: 1613360-1613651 TLCD2
-0.444818675 0.001340945 0.059259314 chr11: 44640598-44641913 CD82
-0.444058521 0 0 chr11: 134094990-134095348 NCAPD3 -0.443736551 0 0
chr1: 152297664-152297679 FLG -0.442245082 0 0 chr18:
8406106-8406859 PTPRM -0.442183213 0 0 chr11: 74178676-74178774
KCNE3 -0.44185294 0 0 chr17: 7951703-7952452 ALOX15B -0.440459014 0
0 chr3: 49213037-49213918 KLHDC8B -0.440313623 0 0 chr2:
219696460-219696809 PRKAG3 -0.440081326 0 0 chr14:
23778024-23780968 BCL2L2 -0.438071628 0 0 chr8: 11182824-11182938
AF131216.6 -0.437271292 0.00048729 0.025803614 chr14:
77843278-77843396 TMED8 -0.436273666 0.002421059 0.07683164 chr8:
22926263-22926692 TNFRSF10B -0.433462746 0 0 chr11:
118550247-118550399 TREH -0.432052092 0 0 chr8: 22471420-22474170
RP11-582J16.5 -0.431261913 0 0 chr14: 76668033-76669134 C14orf118
-0.431248632 0 0 chr7: 83277743-83278479 SEMA3E -0.430438439 0 0
chr8: 109095151-109095913 RSPO2 -0.428973643 0 0 chr6:
42931272-42931618 GNMT -0.427598114 0.000130606 0.007299047 chr1:
24795475-24799466 NIPAL3 -0.426835742 0 0 chrX: 148713225-148713568
TMEM185A -0.426606945 0 0 chr6: 52860046-52860176 GSTA4
-0.426487126 0.002511383 0.077005838 chr11: 4903048-4904113 OR51T1
-0.42646843 0.002258333 0.074896868 chr20: 45362394-45364965
SLC2A10 -0.426321136 0.002038631 0.074404864 chr14:
21167513-21168761 RNASE4 -0.425769874 0.00199731 0.07433842 chrX:
23783663-23784592 ACOT9 -0.424946982 0 0 chr12: 22218054-22218608
CMAS -0.424346307 0.001493347 0.063820363 chr13:
114203739-114204542 TMCO3 -0.423927242 0.001408993 0.06151812 chr7:
127233551-127233665 GCC1 -0.423122614 0 0 chr1: 168211738-168212378
SFT2D2 -0.422864243 0.001012021 0.048756847 chr7: 80551580-80551675
SEMA3C -0.421618187 0.000762726 0.03891404 chr5:
149011544-149014531 ARHGEF37 -0.421113016 0.00166369 0.068211282
chr6: 125583979-125585553 TPD52L1 -0.420885828 0 0 chr22:
39190072-39190148 SUN2 -0.420660125 0 0 chr14: 75201584-75203421
FCF1 -0.420391618 0 0 chr4: 142133947-142134031 RNF150 -0.420201646
0.002267743 0.074896868 chr6: 159420466-159421219 RSPH3
-0.419873459 0 0 chr7: 142637438-142637955 C7orf34 -0.419724438
0.001112591 0.052900521 chr1: 38019606-38019905 SNIP1 -0.417392665
0 0 chr12: 112590538-112591407 TRAFD1 -0.416676004 0.001376789
0.060695692 chr8: 11643471-11644855 NEIL2 -0.415555366 0.000979486
0.047441064 chrX: 99986990-99987110 SYTL4 -0.4151136 0 0 chr1:
11865403-11866977 MTHFR -0.414935432 0 0 chr17: 19578870-19580909
ALDH3A2 -0.414755637 0 0 chr1: 11322501-11322608 MTOR -0.414459145
0 0 chr22: 29449566-29453475 ZNRF3 -0.414121517 0 0 chr6:
3157640-3157809 TUBB2A -0.413596935 0 0 chr17: 12893348-12894960
ARHGAP44 -0.413315388 0 0 chr1: 110888929-110889299 RBM15
-0.413119683 0 0 chr7: 227553-229557 AC145676.2 -0.412677313 0 0
chr21: 39288186-39288749 KCNJ6 -0.412229747 0.00154936 0.065292417
chr13: 21635484-21635718 LATS2 -0.412031798 0 0 chr3:
68981390-68981761 FAM19A4 -0.411387043 0.002212811 0.074896868
chr17: 56032585-56032684 CUEDC1 -0.411227218 0.000689134
0.035558916 chr11: 94861540-94865809 ENDOD1 -0.411164472 0 0 chr9:
5339535-5339873 RLN1 -0.410338259 0.001605749 0.066739616 chr8:
22291403-22291642 SLC39A14 -0.409172508 0.002273186 0.074896868
chrX: 2799092-2800859 GYG2 -0.409121519 0 0 chr5: 10649377-10650308
ANKRD33B -0.408925428 0 0 chr3: 33138210-33138293 TMPPE
-0.408755569 0.002067948 0.074404864 chr17: 74639589-74639894
ST6GALNAC1 -0.408601974 0 0 chr4: 108871400-108874613 CYP2U1
-0.408590838 0 0 chr13: 24476755-24476794 C1QTNF9B -0.4085811 0 0
chr2: 222438569-222438922 EPHA4 -0.408496252 0.002565861
0.077672883 chr7: 99573567-99573780 AZGP1 -0.408221377 0.001762692
0.070831349 chr11: 134188770-134189458 GLB1L3 -0.407453053 0 0
chr15: 90286522-90286868 WDR93 -0.407011464 0 0 chr3:
132086547-132087142 ACPP -0.40512191 0 0 chr1: 154437609-154441926
IL6R -0.404694713 0 0 chr16: 13328886-13329566 SHISA9 -0.404456273
0.00120856 0.054952728 chr3: 184999697-184999778 EHHADH
-0.404337224 0 0 chr7: 30168881-30170096 PLEKHA8 -0.404069681
0.001124581 0.053024689 chr2: 231742722-231743963 ITM2C
-0.404000609 0.001502313 0.064052833 chr15: 43212635-43213007 TTBK2
-0.403995065 0 0 chr5: 78531633-78531861 DMGDH -0.403410254
0.001386979 0.060862399 chr8: 105478884-105479281 DPYS -0.403219685
0.006490479 0.118025771 chr20: 49307662-49308065 FAM65C -0.40278536
0.001873108 0.072385669 chr16: 46796951-46797158 MYLK3 -0.402096842
0.002040434 0.074404864 chr12: 27167010-27167367 TM7SF3
-0.401727922 0.003064993 0.083839548 chr4: 89205557-89205921 PPM1K
-0.400464856 0.001268359 0.057164267 chr6: 160199690-160200144
ACAT2 -0.400341345 0.002969949 0.083014679 chr2:
179914566-179914813 CCDC141 -0.400161772 0 0 chr18:
48604625-48611415 SMAD4 -0.4000199 0.002020762 0.074404864 chr6:
134373515-134373774 SLC2A12 -0.399516711 0 0 chr2:
239198539-239198743 PER2 -0.398648438 0.001529527 0.064908426 chr3:
195808701-195809060 TFRC -0.398416367 0.001122515 0.053024689
chr10: 128994260-128994422 FAM196A -0.397675255 0 0 chr19:
18474200-18480763 PGPEP1 -0.397511696 0.001654324 0.067980724
chr12: 89913184-89918583 GALNT4 -0.3971679 0.000720157 0.036845671
chr8: 27168317-27168836 TRIM35 -0.39698147 0 0 chr12:
112459953-112461255 ERP29 -0.396890381 0 0 chr6:
160534453-160534539 IGF2R -0.396621725 0 0 chr2: 70052587-70053596
ANXA4 -0.396576146 0 0 chr14: 25518412-25519503 STXBP6 -0.396022636
0.00593713 0.114006188 chr15: 90358003-90358094 ANPEP -0.39538808
0.001716149 0.069576817 chr2: 219157188-219157309 TMBIM1
-0.394985318 0.00305971 0.083821279 chr2: 103459870-103460352
TMEM182 -0.393872182 0 0 chr1: 24861582-24863506 RCAN3 -0.392511497
0 0 chrX: 19140559-19140755 GPR64 -0.39247745 0 0 chr2:
130886644-130886795 POTEF -0.392414695 0.000955249 0.046515259
chr2: 231911596-231914434 C2orf72 -0.391887127 0 0 chr8:
142201372-142205907 DENND3 -0.391794001 0.001844172 0.072262867
chr12: 47226109-47226191 SLC38A4 -0.391782093 0.002190198
0.074896868 chr4: 8442374-8442450 ACOX3 -0.391346718 0.005560396
0.110932307 chr17: 65052160-65052913 CACNG1 -0.39017191 0.001934814
0.073518881 chr22: 34318608-34318829 LARGE -0.390149896 0.002219852
0.074896868 chr10: 30404295-30404423 KIAA1462 -0.390135064 0 0
chrX: 12738647-12742642 FRMPD4 -0.390006756 0.002157606 0.074896868
chr4: 75971372-75975325 PARM1 -0.38979558 0.005925405 0.114006188
chr21: 47575383-47575481 FTCD -0.389547561 0 0 chr4:
6619106-6625089 MAN2B2 -0.38950881 0.001332285 0.059043466 chr16:
4986984-4987136 PPL -0.389314121 0 0 chr5: 140389211-140391929
PCDHA4 -0.389058019 0 0 chr1: 150980723-150980854 FAM63A
-0.388539406 0.002205328 0.074896868 chr1: 94312625-94312706 BCAR3
-0.388149966 0 0 chr3: 48340444-48340743 ZNF589 -0.388018199
0.002300474 0.074896868 chr11: 62323634-62323719 AHNAK -0.387645912
0.002464434 0.07690982 chr12: 13366614-13369708 EMP1 -0.387372671
0.001560707 0.065618351 chr16: 56458984-56459448 AMFR -0.387021554
0.003775885 0.092303358 chr17: 17875575-17875784 TOM1L2
-0.386445952 0.001581429 0.066031038 chr10: 115489069-115490662
CASP7 -0.386338815 0.000117675 0.006596685 chr13: 36871773-36871977
C13orf38 -0.386125524 0 0 chr10: 73610938-73611126 PSAP
-0.386051278 0 0 chr12: 63543646-63544722 AVPR1A -0.385980337 0 0
chrX: 70321926-70323385 FOXO4 -0.385961192 0 0 chr6:
149394968-149398126 UST -0.385088054 0.000264232 0.014369004 chr12:
6346928-6347427 CD9 -0.385058406 0.002081356 0.074416668 chr20:
52686971-52687304 BCAS1 -0.384835934 0.001858984 0.072287892 chr6:
36891122-36892331 C6orf89 -0.384372572 0.000705143 0.036281919
chr18: 55253785-55254004 FECH -0.384344223 0.002210942 0.074896868
chr12: 108154733-108155049 PRDM4 -0.384286586 0 0 chr4:
87769891-87770416 SLC10A6 -0.383888948 0 0 chr4:
166418663-166419472 CPE -0.38344051 0 0 chr10: 115423569-115423805
NRAP -0.383262593 0.001199197 0.054952728 chr18: 59560027-59560992
RNF152 -0.382492767 0.002621541 0.078272928 chr21:
34185901-34186053 C21orf62 -0.382395766 0 0 chr1:
114515645-114520426 HIPK1 -0.382102457 0.003983912 0.094835898
chr1: 235813848-235814054 GNG4 -0.382028045 0.006734515 0.120383578
chr20: 36151068-36152092 NNAT -0.381520055 0 0 chr4:
141677069-141677274 TBC1D9 -0.381389837 0.007537688 0.126765765
chr15: 90293739-90294541 MESP1 -0.381319191 0 0 chr17:
65026581-65029518 CACNG4 -0.380258212 0.003303945 0.085620014
chr21: 43735402-43735761 TFF3 -0.37982593 0 0 chrX:
71363102-71363424 NHSL2 -0.379789027 0.003306045 0.085620014 chr9:
117568082-117568406 TNFSF15 -0.379635338 0.001517712 0.064557866
chr4: 111563074-111563279 PITX2 -0.379432657 0.003164641
0.084777841 chr7: 7575380-7575484 COL28A1 -0.379174401 0.003048335
0.083821279 chr1: 19983358-19984945 NBL1 -0.379105575 0.005009103
0.104695438 chr17: 7990613-7991022 ALOX12B -0.37885261 0.004112088
0.09575366 chr4: 114899592-114900883 ARSJ -0.378760672 0.008790649
0.13508 chr17: 19237268-19240028 EPN2 -0.378663398 0 0 chr1:
162749901-162750237 DDR2 -0.378539319 0.004597198 0.100359255
chr10: 117704168-117708503 ATRNL1 -0.378216284 0 0 chr15:
39887562-39891119 THBS1 -0.378209064 0 0 chr7: 51384289-51384515
COBL -0.378105277 0 0 chr7: 6590638-6591067 GRID2IP -0.378036482 0
0 chr13: 36047925-36050832 MAB21L1 -0.377665681 0.002616639
0.078272928 chr5: 171433461-171433877 FBXW11 -0.377240049
0.001478969 0.063564631 chr16: 20911525-20911706 DCUN1D3
-0.377176749 0.001548826 0.065292417 chr2: 61148897-61150645 REL
-0.377068408 0 0 chr2: 175351600-175351822 GPR155 -0.376758939
0.001703413 0.069486359 chr4: 110222878-110223813 COL25A1
-0.376530527 0 0 chr16: 16317255-16317351 ABCC6 -0.376524916
0.002250961 0.074896868 chr14: 55611833-55612147 LGALS3
-0.376477741 0.001813224 0.07142087 chr11: 6631692-6632102 ILK
-0.376273373 0 0 chr20: 8000084-8000476 TMX4 -0.37620338
0.002797436 0.080691396 chr2: 23929350-23931481 KLHL29 -0.375178691
0.003023736 0.0837197 chr11: 30608288-30608419 MPPED2 -0.375114316
0.002532313 0.077155474 chr8: 30585046-30585443 GSR -0.375065559
0.000240196 0.013260404 chr9: 91606384-91611055 C9orf47
-0.375058726 0.001854016 0.072262867 chr18: 71958981-71959251 CYB5A
-0.374903816 0.002292426 0.074896868 chr10: 43623559-43625799 RET
-0.374655986 0.00408246 0.095677062 chr6: 143266235-143266338
HIVEP2 -0.374655117 0.004838503 0.102307014 chr11:
74022456-74022702 P4HA3 -0.37407796 0.003297931 0.085620014 chr1:
184006228-184006863 GLT25D2 -0.373798797 0 0 chr14:
21161705-21162338 ANG -0.373610746 0.000947353 0.046379462 chr15:
55581913-55582001 RAB27A -0.372372329 0.004349301 0.09789861 chr21:
48084206-48085036 PRMT2 -0.372320011 0.002611429 0.078272928 chr12:
130387805-130388211 TMEM132D -0.372252514 0.002436548 0.07683164
chr16: 66516774-66519747 AC132186.2 -0.372011859 0 0 chr3:
119483898-119485949 C3orf15 -0.371762952 0.002076929 0.074404864
chr11: 71707240-71708643 RNF121 -0.371621829 0 0 chr16:
71883526-71891231 ATXN1L -0.371120686 0 0 chr19: 38886119-38886868
SPRED3 -0.370771544 0.002710805 0.07954175 chr15: 78461263-78464291
IDH3A -0.370762369 0.005599722 0.111134243 chr17: 42255572-42256451
ASB16 -0.370554636 0.002239895 0.074896868 chr19: 57351949-57352097
ZIM2 -0.370474327 0.009388443 0.140270167 chr15: 32695347-32695396
RP13- -0.370325092 0.000183582 0.010196928 395E19.1 chr1:
214725657-214725792 PTPN14 -0.369408066 0.005749033 0.112400084
chr15: 84962535-84966399 CSPG4P5 -0.369128441 0.002286269
0.074896868 chr18: 19284464-19284766 ABHD3 -0.369063411 0.002353978
0.075673086 chr3: 113005521-113006303 BOC -0.36895421 0.001134915
0.053127463
chr22: 30685281-30685616 GATSL3 -0.368746426 0.001870578
0.072385669 chr15: 42783294-42783336 ZFP106 -0.368565346
0.003731514 0.091793135 chr19: 48700486-48700877 C19orf68
-0.36851038 0 0 chrX: 120181461-120183794 GLUD2 -0.368504069
0.003279187 0.085620014 chrX: 47064319-47065264 INE1 -0.368175848
0.001988041 0.07433842 chr5: 125930698-125931110 ALDH7A1
-0.367952163 0.002483797 0.076926292 chr12: 10374385-10375727
GABARAPL1 -0.367831123 0.005297504 0.108851661 chr1:
209907648-209908295 HSD11B1 -0.367714675 0.003052939 0.083821279
chr22: 40366908-40369725 GRAP2 -0.367292326 0.003208892 0.085084821
chr2: 171572768-171574588 SP5 -0.367283441 0.002630479 0.078272928
chr10: 102745374-102745628 SEMA4G -0.366880776 0 0 chr11:
33757927-33757991 CD59 -0.366726455 0.003215396 0.085133002 chr16:
69152257-69152622 HAS3 -0.366420617 0.00095903 0.046574504 chr9:
119158787-119164601 PAPPA -0.365815146 0.00627853 0.116920758 chr2:
227659704-227664475 IRS1 -0.365509755 0.002014141 0.074404864
chr19: 46148530-46148726 EML2 -0.364924449 0 0 chr21:
38639538-38640262 DSCR3 -0.364678478 0.004475788 0.098672627 chr7:
79082335-79082890 MAGI2 -0.364612272 0.005047787 0.105261723 chr12:
102079359-102079796 MYBPC1 -0.364376297 0.007651984 0.127947875
chr12: 57350933-57351418 RDH16 -0.364373561 0.004448539 0.098538814
chr15: 42500278-42500514 VPS39 -0.364232582 0.002353503 0.075673086
chr14: 81864638-81864927 STON2 -0.364230778 0.004382182 0.098116492
chr7: 91771776-91772266 CYP51A1 -0.364210127 0 0 chr3:
159614511-159615149 SCHIP1 -0.364186792 0.002167089 0.074896868
chr2: 238820169-238820756 RAMP1 -0.363626284 0.00164314 0.067674286
chr22: 36054661-36057404 APOL6 -0.363509609 0.00456657 0.099888173
chr12: 78604177-78606790 NAV3 -0.363115626 0.003889133 0.094210495
chr15: 71407467-71407839 CT62 -0.362619907 0.000302258 0.016339042
chr1: 182359631-182361341 GLUL -0.362222252 0.00311835 0.084283617
chr6: 144385587-144385735 PLAGL1 -0.36221699 0.006059476 0.11560742
chr18: 57364443-57364574 CCBE1 -0.361989182 0.001160655 0.0540538
chr9: 108536145-108538893 TMEM38B -0.36183798 0.003196865
0.085052362 chr7: 121784214-121784334 AASS -0.361635356 0.001030161
0.049499517 chr2: 230135729-230136001 PID1 -0.361364734 0.007876988
0.129133025 chr4: 37687821-37687998 RELL1 -0.361328155 0.004421037
0.098285551 chr16: 69166386-69166487 CHTF8 -0.360655997 0.00397391
0.094764506 chr1: 184943433-184943682 FAM129A -0.360529444
0.003171679 0.084841251 chr12: 56112874-56113871 BLOC1S1
-0.360332424 0.002460351 0.07690982 chr5: 40691880-40693837 PTGER4
-0.360302037 0 0 chr20: 48098450-48099184 KCNB1 -0.360156699
0.005928121 0.114006188 chr14: 91282518-91282761 TTC7B -0.36000688
0.002911014 0.08228265 chr2: 169721343-169722024 NOSTRIN
-0.359423859 0.002183004 0.074896868 chr19: 47290656-47291851
SLC1A5 -0.358711445 0 0 chr2: 111875192-111875799 ACOXL
-0.358659464 0.00272735 0.079641256 chr7: 84815993-84816171 SEMA3D
-0.358554714 0.008937979 0.1364206 chr16: 75528837-75529282 CHST6
-0.358161822 0 0 chr1: 46216268-46216322 IPP -0.358130707
0.002061859 0.074404864 chr15: 30706317-30706463 AC019322.1
-0.35739784 0.003295666 0.085620014 chr9: 4662297-4665256 PPAPDC2
-0.357393072 0.008539527 0.133479717 chr14: 23904828-23904927 MYH7
-0.357022956 0.000251827 0.013818534 chr5: 42887392-42887494 SEPP1
-0.356433723 0.004618262 0.10049394 chr10: 53455246-53459355 CSTF2T
-0.356077989 0.005394785 0.109381082 chr1: 82456074-82458107 LPHN2
-0.35586493 0.00872594 0.134884462 chr20: 5170747-5178533 CDS2
-0.355827803 0.001959211 0.074231845 chr14: 20881563-20881580 TEP1
-0.355558706 0 0 chr17: 62207335-62207502 ERN1 -0.355198611
0.003341644 0.085969228 chr22: 24890657-24891042 C22orf45
-0.355112593 0.006216471 0.116920758 chr7: 148112508-148118090
CNTNAP2 -0.355018684 0.003900583 0.094210495 chrX:
100786630-100788446 ARMCX4 -0.354773706 0.001780023 0.071212674
chr9: 100845127-100845357 NANS -0.354741743 0.00322612 0.085267223
chr11: 85338261-85338966 DLG2 -0.35458979 0.007531741 0.126765765
chr10: 36810648-36813162 NAMPTL -0.354542215 0.003272356
0.085620014 chr3: 51418480-51421629 DOCK3 -0.354499487 0.009000821
0.136900167 chr11: 119170204-119177651 CBL -0.354474684 0 0 chr7:
92465791-92465908 CDK6 -0.354190236 0.007309538 0.124777387 chrX:
110463585-110464173 PAK3 -0.353473303 0.00372339 0.091761103 chr1:
213445866-213448116 RPS6KC1 -0.353132762 0.008090944 0.130860029
chr1: 203144678-203144941 MYBPH -0.353031224 0 0 chr12:
110205816-110208312 C12orf34 -0.352927122 0.003855714 0.093875787
chr1: 54483764-54483856 LDLRAD1 -0.352368395 0.002200147
0.074896868 chr8: 92052871-92053292 TMEM55A -0.352125583 0.00424435
0.096531516 chr15: 90890818-90892669 GABARAPL3 -0.352096621
0.004075199 0.09564239 chr5: 126801297-126801429 MEGF10
-0.351979071 0.005769117 0.112671479 chr7: 66273872-66276446 KCTD7
-0.351787458 0.008500777 0.133361292 chr12: 101521638-101522419
ANO4 -0.351661205 0.00536422 0.109252525 chr6: 3231790-3231964
TUBB2B -0.350836048 0.00415823 0.095871025 chr14: 76446884-76448092
TGFB3 -0.350820631 0.007016608 0.121921113 chr2:
178972980-178973081 PDE11A -0.350337632 0.005792206 0.113000905
chr11: 114121047-114121398 ZBTB16 -0.349982548 0.007051836
0.122091644 chr3: 97471032-97471304 EPHA6 -0.349748772 0.004669226
0.100960902 chr18: 72775105-72777628 ZNF407 -0.349595533
0.011713078 0.154835981 chr17: 40540296-40540449 STAT3 -0.349348115
0 0 chr16: 90095315-90096309 C16orf3 -0.349062505 0.002890689
0.082124567 chr17: 76899215-76899297 AC100788.1 -0.349055229
0.004954969 0.104163323 chr2: 11780416-11782914 GREB1 -0.348390425
0.004885601 0.103182756 chr3: 169487108-169487683 AC078802.1
-0.348375436 0.006616271 0.118981508 chr15: 64126025-64126147 HERC1
-0.348284478 0.004634897 0.10069813 chr7: 102301592-102301847
RP11-577H5.4 -0.348203645 0 0 chr2: 169764077-169766505 G6PC2
-0.347521745 0.000531991 0.027845969 chr10: 127697622-127698161
FANK1 -0.346440794 0.003260067 0.085620014 chr1: 68153343-68154021
GADD45A -0.346346476 0.008456687 0.133216661 chr14:
93651154-93651260 MOAP1 -0.34606439 0 0 chr9: 102625901-102629173
NR4A3 -0.346030498 0.004972561 0.10429172 chr20: 42939615-42939809
FITM2 -0.345997257 0.004756964 0.101816018 chr2:
239139841-239140318 AC016757.3 -0.3458947 0.004187488 0.096032
chr4: 175443509-175444305 HPGD -0.345861904 0.002242854 0.074896868
chr1: 24740163-24743424 C1orf201 -0.345686354 0.005986125
0.114759271 chr1: 113499460-113499635 SLC16A1 -0.345488279
0.009716079 0.142148692 chr10: 14816251-14816896 FAM107B
-0.345316938 0.001800119 0.071315614 chr12: 85429981-85430055
TSPAN19 -0.345103145 0.006226591 0.116920758 chr16:
88634958-88636548 C16orf85 -0.345097604 0.001129539 0.053024689
chr4: 100212053-100212185 ADH1A -0.344998373 0.004254851
0.096531516 chr8: 1728415-1734738 CLN8 -0.344633185 0.010423843
0.14552518 chr11: 67124213-67124443 POLD4 -0.344486773 0.002625331
0.078272928 chr14: 102964439-102968809 TECPR2 -0.344287946
0.00249821 0.076926292 chr19: 45826078-45826233 CKM -0.344265976
0.002432096 0.07683164 chr6: 20212366-20212670 MBOAT1 -0.343916793
0.005876217 0.113663186 chr9: 130869307-130871524 SLC25A25
-0.343624793 0 0 chr9: 86258343-86259045 C9orf103 -0.343444827
0.002600596 0.078272928 chr11: 626020-626078 CDHR5 -0.343187787
0.008441373 0.133216661 chr16: 88729418-88729518 MVD -0.343137668
0.004619966 0.10049394 chr12: 52470569-52471278 C12orf44
-0.343056136 0.000630237 0.032893644 chr3: 143767509-143767561
C3orf58 -0.342328768 0.006331044 0.117217889 chr16:
76592386-76593135 CNTNAP4 -0.342102919 0.000790908 0.040014672
chr6: 139113885-139114456 CCDC28A -0.341986012 0.006517637
0.118025771 chr17: 33513317-33516364 UNC45B -0.341937241
0.003818629 0.093222797 chr10: 135336774-135337062 RP11-
-0.341903564 0.006813291 0.120821721 108K14.4 chr2:
242162600-242164792 ANO7 -0.341869694 0.007132564 0.123028262 chr4:
7940727-7942023 AC097381.1 -0.341732589 0.008108444 0.131026389
chr19: 35614344-35615227 FXYD3 -0.341197928 0.006740632 0.120383578
chr10: 81373492-81375197 SFTPA1 -0.341146486 0.001850992
0.072262867 chr11: 125301061-125303285 PKNOX2 -0.341144084
0.003301426 0.085620014 chr8: 27401960-27403081 EPHX2 -0.34107733
0.004448705 0.098538814 chr16: 81411019-81413940 GAN -0.341026233
0.002661769 0.078610908 chr2: 179695391-179695529 TTN -0.340871763
0.003439286 0.087240779 chr3: 49761030-49761384 GMPPB -0.340818196
0.006392303 0.117755656 chr11: 125366403-125369424 AP000708.1
-0.340419481 0.007994613 0.12969294 chr8: 27337285-27337400 CHRNA2
-0.340317829 0.01017339 0.143603022 chr6: 170713850-170716153
FAM120B -0.340145296 0.006394353 0.117755656 chr19:
52034835-52035110 SIGLEC6 -0.339935646 0.00249674 0.076926292 chr2:
169952053-169952677 DHRS9 -0.339663644 0 0 chr8:
121825324-121825513 SNTB1 -0.339220559 0.013026815 0.159180228
chr10: 61122866-61122939 FAM13C -0.339116788 0.012107259
0.155429477 chr7: 98030113-98030380 AC093799.1 -0.339089857
0.002803296 0.080691396 chr5: 131630870-131631008 P4HA2
-0.338862866 0.004018835 0.095037797 chrX: 112083679-112084043 AMOT
-0.338743263 0.009557513 0.141580566 chr3: 113346492-113348425
SIDT1 -0.338182328 0.016461828 0.175467239 chr1:
111893880-111895635 C1orf88 -0.337856332 0.00901587 0.136919096
chr13: 111521577-111522162 C13orf29 -0.33775445 0.002559298
0.077611339 chr1: 201860927-201861434 SHISA4 -0.337716435
0.002153764 0.074896868 chr11: 134019040-134021896 JAM3
-0.337708293 0.002445067 0.07690982 chr7: 49951629-49952138 VWC2
-0.33764517 0.005162659 0.106835773 chr12: 46663762-46663800
SLC38A1 -0.33763681 0.009933718 0.143081782 chr17:
71258247-71258491 CPSF4L -0.337524821 0.006504807 0.118025771 chr1:
156108870-156109880 LMNA -0.337501786 0 0 chr19: 30205813-30206364
C19orf12 -0.337294662 0.009407927 0.140292428 chr7:
134264258-134264592 AKR1B15 -0.337020674 0.005585004 0.111106714
chr7: 4897363-4901625 PAPOLB -0.336643583 0.009833222 0.142636167
chr2: 11317862-11319000 PQLC3 -0.33652056 0.013477235 0.162218034
chr14: 39900767-39901704 FBXO33 -0.336362403 0.004102791 0.09575366
chr9: 131703723-131704320 PHYHD1 -0.336138287 0 0 chr1:
221915322-221915518 DUSP10 -0.33590192 0.012733827 0.158213348
chr3: 41301355-41301587 CTNNB1 -0.335633668 0.006267131 0.116920758
chr4: 31144094-31144728 PCDH7 -0.335237096 0.005140064 0.106574171
chr1: 203765436-203769686 ZBED6 -0.335082465 0.003469323
0.087293121 chr19: 3543826-3544028 C19orf71 -0.334820013
0.004225675 0.096464363 chr22: 43117170-43117304 A4GALT -0.33461522
0 0 chr15: 99791359-99791422 TTC23 -0.334607361 0.009988191
0.143216183 chr16: 5064859-5069156 SEC14L5 -0.334522135 0 0 chr5:
32786339-32787256 NPR3 -0.334311711 0.005412112 0.10946569 chr2:
160918805-160919121 PLA2R1 -0.334063845 0.005422954 0.109562966
chr4: 108955394-108956331 HADH -0.334047223 0.005989748 0.114759271
chr3: 14814297-14814541 C3orf20 -0.333760773 0.004507549
0.099237103 chr20: 55100838-55100981 GCNT7 -0.333749414 0.008434475
0.133216661 chr10: 43762292-43762367 RASGEF1A -0.333319387
0.001430906 0.06194304 chr5: 80561957-80562216 CKMT2 -0.333284313
0.005483096 0.109968839 chr6: 41031839-41032465 APOBEC2
-0.333213576 0.004677515 0.10098106 chr9: 5304369-5304969 RLN2
-0.333058195 0.005460123 0.109968839 chr1: 181057637-181059977 IER5
-0.332972834 0 0 chr12: 50236168-50236912 BCDIN3D -0.332717732
0.007849382 0.129133025 chr14: 95942014-95942173 C14orf49
-0.332614322 0.008380922 0.133216661 chr13: 24247510-24250232
TNFRSF19 -0.332405917 0.0118646 0.155153269 chr3: 38178355-38178733
ACAA1 -0.332380373 0.005375471 0.109333343 chr10: 62761156-62761198
RHOBTB1 -0.332293978 0.008639609 0.134263631 chr14:
24114350-24114848 DHRS2 -0.332200435 0.009216563 0.138576518 chr19:
53077329-53077383 ZNF808 -0.332184126 0.004142985 0.095871025 chrX:
67944146-67945684 STARD8 -0.332156945 0.005297851 0.108851661
chr22: 17612504-17612994 AC006946.15 -0.332029863 0.002076087
0.074404864 chr15: 100273489-100273766 LYSMD4 -0.33196355
0.004818502 0.102159863 chr19: 57802066-57805436 ZNF460
-0.331805696 0.0062541 0.116920758 chr1: 110052041-110052360 AMIGO1
-0.331748977 0.007140297 0.12304479 chr19: 40931773-40931932
SERTAD1 -0.331603747 0.004097877 0.09575366 chr1:
235667440-235667781 B3GALNT2 -0.331355681 0.006921811 0.121704609
chr5: 180631588-180632293 TRIM7 -0.331070531 0.00478817 0.102074564
chr7: 134849169-134850650 TMEM140 -0.330961226 0.006462905
0.118025771 chr1: 203054618-203055164 MYOG -0.330806046 0 0 chr22:
24836550-24838328 ADORA2A -0.330604462 0.009903173 0.143081782
chr14: 59950207-59951148 C14orf149 -0.330342745 0.011107988
0.150003266 chr17: 62833173-62833243 AC103810.1 -0.330067269
0.004228881 0.096464363 chr3: 159614511-159615155 IQCJ-SCHIP1
-0.329859948 0.000512092 0.026881861 chr22: 43411026-43411151
PACSIN2 -0.329641143 0.00529232 0.108851661 chr3:
143566989-143567373 SLC9A9 -0.329499509 0.00957653 0.141580566
chr6: 147705849-147708707 STXBP5 -0.329411447 0.005615759
0.111134243 chr10: 43991463-43991517 ZNF487P -0.329209459
0.004820294 0.102159863 chr6: 123384818-123385612 CLVS2
-0.328460279 0.004405369 0.098228128 chr2: 168114366-168116263
XIRP2 -0.328456174 0.001905952 0.07290082 chr11: 70281131-70282690
CTTN -0.328378509 0.005485425 0.109968839 chr1: 39876150-39882154
KIAA0754 -0.328304607 0.009074575 0.137166781 chr21:
47648347-47648738 LSS -0.32811765 0.006302121 0.116920758 chr8:
75233143-75233563 JPH1 -0.327851537 0.005395884 0.109381082 chr17:
46135656-46138906 NFE2L1 -0.327788072 0.002131117 0.074896868 chr3:
196065134-196065374 TM4SF19 -0.327643438 0.004075715 0.09564239
chr17: 11461070-11462196 SHISA6 -0.327641088 0.003501168 0.08783387
chr7: 97841565-97842271 BHLHA15 -0.327621915 0.007927854
0.129538147 chr11: 4730834-4731698 AC103710.1 -0.327522873
0.003710943 0.091703214 chr10: 75457290-75457639 AGAP5 -0.327417008
0.00230532 0.074904336 chr2: 204599506-204602557 CD28 -0.327340798
0.003182194 0.084997327 chr1: 200143090-200146552 NR5A2
-0.327072728 0.000350694 0.01878955 chr5: 140890513-140892542
PCDHGC3 -0.326986718 0 0 chr17: 4926762-4931696 KIF1C -0.326823547
0.00581312 0.11307866 chr2: 182794287-182795465 SSFA2 -0.326707409
0.006909184 0.121600292 chr6: 159240348-159240444 EZR -0.326642824
0.006782665 0.120633891 chr8: 12613432-12613582 LONRF1 -0.326542762
0.001910521 0.07290082 chr11: 111789401-111789574 AP000907.1
-0.326455419 0.006026463 0.115098472 chr8: 74235147-74237516 RDH10
-0.326283654 0 0 chr9: 36276890-36277053 GNE -0.326253035
0.007726033 0.128531382 chr11: 66725792-66725847 PC -0.32597854
0.002534333 0.077155474 chr14: 23834216-23834961 EFS -0.325910554
0.005541994 0.110736224 chr17: 46198596-46200105 SNX11 -0.325404034
0.00435117 0.09789861 chr22: 50450973-50451088 IL17REL -0.325024492
0.006764548 0.120633891 chr21: 34265885-34266043 C21orf49
-0.324901611 0.003697375 0.091617209 chr5: 135223720-135224326
SLC25A48 -0.324491441 0.004700972 0.101165586 chr11:
31451817-31453396 DNAJC24 -0.324035319 0.007961992 0.12969294
chr16: 69117387-69119083 TMCO7 -0.323930714 0.001996814 0.07433842
chr11: 5256444-5256600 HBD -0.323415761 0.006496377 0.118025771
chr11: 60543077-60544205 MS4A15 -0.323306954 0.005827077
0.113194863 chr19: 34991033-34992085 WTIP -0.323288091 0.003628394
0.09052543 chr21: 33765077-33765335 URB1 -0.322605234 0.007661761
0.127947875 chr11: 107590341-107590419 SLN -0.32259301 0.003198302
0.085052362 chr1: 16332413-16335302 C1orf64 -0.322571114
0.003329308 0.085908111 chr14: 52793938-52795324 PTGER2 -0.32254401
0.00584014 0.113206474 chr7: 100734918-100735017 TRIM56 -0.32209346
0.006276926 0.116920758 chr4: 6302383-6304992 WFS1 -0.321869596
0.006860626 0.121215509 chr14: 65007185-65009955 HSPA2 -0.321607655
0.004372355 0.098043319 chr10: 92680757-92681033 ANKRD1 -0.32149868
0.004154414 0.095871025 chr2: 169887734-169887832 ABCB11
-0.321337647 0 0 chr2: 100937876-100939195 LONRF2 -0.321330932
0.006819887 0.120821721 chr3: 9934492-9936033 JAGN1 -0.32116212
0.00609355 0.116013774 chr7: 1097127-1098897 GPR146 -0.320796122
0.005512112 0.110317975 chr22: 24236884-24237414 MIF -0.320238374
0.003304999 0.085620014 chr10: 17171642-17171830 CUBN -0.3201406
0.006228317 0.116920758 chr11: 70052238-70053496 FADD -0.320086207
0.005320566 0.109004718 chr10: 120355027-120355160 PRLHR
-0.319837349 0.001458704 0.062932162 chr1: 6674509-6674667 KLHL21
-0.319337027 0.004808398 0.102159863 chr1: 167095023-167098402
DUSP27 -0.31926543 0.003356573 0.086049007 chr5:
176730009-176730745 RAB24 -0.319255928 0.003368433 0.086049007
chr20: 55093142-55093943 C20orf43 -0.319042706 0.006112598
0.116162907 chr5: 140389211-140391929 PCDHA13 -0.318776843
0.005901557 0.113959318
chr4: 186320723-186321782 ANKRD37 -0.318309287 0.006407439
0.117791816 chrX: 138790264-138790386 MCF2 -0.318200097 0.003906063
0.094217569 chr12: 124242473-124245549 ATP6V0A2 -0.318185391
0.005692545 0.112019177 chr2: 211179634-211179914 MYL1 -0.318151264
0.004475644 0.098672627 chr1: 232172439-232177018 DISC1
-0.317969164 0.006350874 0.117465307 chr9: 99381500-99382112 CDC14B
-0.317910194 0.004163307 0.095871025 chr1: 223175726-223179337
DISP1 -0.317844696 0.003050324 0.083821279 chr12: 53646601-53648189
MFSD5 -0.317723142 0 0 chr22: 50050271-50051190 C22orf34
-0.317628122 0.004257102 0.096531516 chr6: 30523907-30525008 GNL1
-0.317139954 0 0 chr3: 11596284-11599139 ATG7 -0.3169458
0.002281379 0.074896868 chr16: 71264464-71264625 HYDIN -0.316806117
0.004731057 0.101554491 chr11: 125136535-125136741 RP11-
-0.316600832 0.003883559 0.094210495 687M24.6 chr12:
113797134-113797298 SLC24A6 -0.315121613 0.004109022 0.09575366
chr11: 66113960-66115163 B3GNT1 -0.314657476 0.00480751 0.102159863
chr7: 128498389-128499328 FLNC -0.312046294 0.006196778 0.116920758
chr11: 35441454-35441610 SLC1A2 -0.311887865 0.004570119
0.099888173 chr20: 61167650-61167971 C20orf166 -0.311455851
0.006090275 0.116013774 chrX: 37312388-37316548 PRRG1 -0.311450759
0.002311383 0.074967239 chr6: 3152721-3153812 BPHL -0.311242496
0.003734797 0.091793135 chr7: 31697884-31698334 CCDC129
-0.311051556 0.002109037 0.074896868 chr1: 26393826-26394927 TRIM63
-0.309913705 0.005735635 0.112400084 chr20: 6034475-6034695 LRRN4
-0.309273385 0.001724002 0.069739517 chr5: 80689806-80689998 ACOT12
-0.308117282 0.003117847 0.084283617 chr8: 33330581-33330940 FUT10
-0.307474854 0.003443905 0.087240779 chr1: 182558301-182558391
RNASEL -0.307317477 0.005481298 0.109968839 chr7:
107443555-107443670 SLC26A3 -0.307261592 0.003057062 0.083821279
chr10: 76868766-76868976 DUSP13 -0.306383849 0.004406938
0.098228128 chr19: 54984210-54984411 CDC42EP5 -0.305854117
0.002282771 0.074896868 chrX: 118699087-118699397 CXorf56
-0.304902726 0.002049412 0.074404864 chr11: 34492914-34493609 CAT
-0.303602311 0.004918322 0.103512716 chr15: 101454905-101456831
ALDH1A3 -0.303374031 0.005729864 0.112400084 chr17:
10325246-10325267 MYH8 -0.303265671 0.001915237 0.072927569 chr1:
45792544-45794347 HPDL -0.302015312 0.005632886 0.111327654 chr1:
162838442-162838605 C1orf110 -0.300571972 0 0 chr6:
39869588-39872648 DAAM2 -0.299895021 0.00330218 0.085620014 chr11:
68855342-68858072 TPCN2 -0.299814629 0.004906377 0.103387608 chr2:
28634745-28640179 FOSL2 -0.299377859 0.004661807 0.100960902 chr22:
20137990-20138399 AC006547.14 -0.295216407 0.002654087 0.078584121
chr19: 4867620-4867780 PLIN3 -0.292601141 0.005346359 0.109247654
chrX: 152760831-152760978 HAUS7 -0.289026884 0.00546317 0.109968839
chr7: 54636701-54638773 VSTM2A -0.286077172 0.004209951 0.096303956
chr5: 180000987-180005405 CNOT6 0.280162496 0.004272958 0.096770254
chr8: 56685785-56685966 TMEM68 0.280739417 0.004369285 0.098043319
chr14: 97031291-97033425 PAPOLA 0.28154747 0.002912941 0.08228265
chr8: 66545953-66546442 ARMC1 0.281785249 0.005362125 0.109252525
chr15: 49170297-49172190 EID1 0.288853949 0.005164445 0.106835773
chr1: 226496809-226497570 LIN9 0.291829568 0.004543724 0.099671077
chr17: 57970057-57970296 TUBD1 0.293182401 0.004441351 0.098538814
chr4: 148593017-148593195 TMEM184C 0.293710605 0 0 chr15:
38776455-38779911 FAM98B 0.294672563 0.002073568 0.074404864 chr20:
47712344-47713489 CSE1L 0.296532783 0.002844634 0.081237547 chr5:
56558420-56560505 GPBP1 0.297506006 0 0 chr12: 58350469-58351052
XRCC6BP1 0.298404618 0.005616981 0.111134243 chr19:
44284854-44285409 KCNN4 0.299794156 0.001595016 0.066445584 chr17:
30325676-30328064 SUZ12 0.300313931 0.002768918 0.080210303 chr5:
140698056-140700330 TAF7 0.30034378 0.004413046 0.098228128 chr1:
185069331-185071740 RNF2 0.300817006 0.002256081 0.074896868 chr17:
58023911-58027925 RPS6KB1 0.301654892 0.002463315 0.07690982 chr1:
151881835-151882284 THEM4 0.303048607 0.003891008 0.094210495 chr3:
196555189-196559518 PAK2 0.304684107 0.00565642 0.111550003 chr3:
56655559-56655846 CCDC66 0.305496446 0.004722128 0.101500611 chr9:
130457272-130457460 STXBP1 0.306449217 0.002610067 0.078272928
chr6: 84418064-84419410 SNAP91 0.306744409 0.00289378 0.082124567
chr18: 267965-268059 THOC1 0.308452954 0.002246863 0.074896868
chr11: 126174102-126174213 RP11-712L6.5 0.308555738 0.001968874
0.074231845 chr1: 92764481-92764544 GLMN 0.309420667 0.005838193
0.113206474 chr5: 68709857-68710628 RAD17 0.309947634 0.002036157
0.074404864 chr12: 51566083-51566926 TFCP2 0.310337811 0.002022616
0.074404864 chr12: 133532828-133532892 ZNF605 0.310370533
0.005741782 0.112400084 chr3: 69129484-69129559 UBA3 0.311955874
0.004476434 0.098672627 chr2: 44222912-44223144 LRPPRC 0.311969209
0.005806947 0.11307866 chr12: 106697789-106698057 CKAP4 0.31330448
0.005323305 0.109004718 chr19: 11978120-11980306 ZNF439 0.31399977
0.000679969 0.03518595 chr17: 30714772-30714780 ZNF207 0.314664535
0.004663714 0.100960902 chr3: 178984436-178984790 KCNMB3
0.315313767 0.000492826 0.026020926 chr3: 3192223-3192563 TRNT1
0.315943006 0.005904075 0.113959318 chr2: 37193372-37193615 STRN
0.316227369 0.004355122 0.09789861 chr19: 34718269-34720420 LSM14A
0.316229966 0.005347198 0.109247654 chr5: 86708251-86708836 CCNH
0.31651571 0.002288526 0.074896868 chr19: 12662143-12662327 ZNF564
0.316577163 0.001969925 0.074231845 chr19: 23941548-23941693 ZNF681
0.316870966 0.003718019 0.091753239 chr2: 203103162-203103331 SUMO1
0.317470493 0.00313409 0.08454882 chr11: 85563599-85565986
AP000974.1 0.31748757 0.00585565 0.113386114 chr14:
39649706-39652422 PNN 0.317832199 0.006385595 0.117755656 chr8:
142012112-142012315 PTK2 0.318325276 0.003146205 0.084658552 chr20:
57617753-57617964 SLMO2 0.319001046 0.005278416 0.108821635 chr13:
47371239-47371367 ESD 0.319016641 0.003463992 0.087293121 chr21:
40721385-40721573 HMGN1 0.319212709 0 0 chr7: 79846618-79848718
GNAI1 0.320340043 0.004411903 0.098228128 chr19: 57764440-57774106
ZNF805 0.320363681 0.005385112 0.109381082 chr16: 3367189-3368574
ZNF75A 0.320482104 0.002181862 0.074896868 chr15: 60771201-60771344
NARG2 0.321091259 0.004175977 0.095889084 chr17: 8286474-8286568
RPL26 0.321101419 0.003760575 0.092052993 chr6: 168720067-168720434
DACT2 0.321179692 0.002407179 0.076804143 chr14: 35008760-35008943
EAPP 0.321340899 0.004534668 0.099592725 chr2: 99921102-99921205
LYG1 0.321471395 0.0062296 0.116920758 chr13: 41701704-41706882
KBTBD6 0.321594919 0.004173426 0.095889084 chr5:
140602930-140605858 PCDHB14 0.322104178 0.006233177 0.116920758
chr12: 75905292-75905416 KRR1 0.322196506 0 0 chr7:
29552179-29553944 CHN2 0.322296255 0.002750261 0.080052876 chr19:
19843764-19843921 ZNF14 0.322336899 0.004015145 0.095037797 chr11:
75851754-75854239 UVRAG 0.322461087 0.005592429 0.111132704 chr3:
93747210-93747454 STX19 0.322908263 0.006898306 0.121600292 chr17:
65739858-65740318 NOL11 0.323132613 0.00348465 0.087540376 chr16:
28331396-28335170 SBK1 0.324007796 0.005584472 0.111106714 chr11:
125825711-125826214 RP11- 0.324171654 0.007187233 0.123441982
680F20.6 chrY: 21765682-21768160 CYorf15B 0.324250683 0 0 chr15:
59949322-59949740 GTF2A2 0.324886639 0.00679345 0.120633891 chr8:
141524392-141527236 CHRAC1 0.325103238 0.006576969 0.1185295 chr1:
46153654-46153785 GPBP1L1 0.325228449 0.00663606 0.119219352 chr18:
33558797-33559241 C18orf21 0.325286794 0.00452516 0.099504209
chr19: 35174896-35177302 ZNF302 0.325802707 0.003260401 0.085620014
chr4: 170192009-170192256 SH3RF1 0.326613568 0.008264705
0.132373754 chr10: 74927623-74927853 ECD 0.326731314 0.005005407
0.104695438 chr5: 170738392-170739138 TLX3 0.326740102 0.007724752
0.128531382 chr2: 217069910-217071026 XRCC5 0.327063734 0.004964977
0.104253046 chr16: 3458320-3459370 ZNF174 0.32719442 0.005999522
0.114825412 chr8: 82644987-82645138 ZFAND1 0.327291564 0.004906685
0.103387608 chr2: 238166072-238166319 AC112715.2 0.327628695
0.006988291 0.121921113 chr22: 41252434-41253026 ST13 0.327785232
0.006664518 0.119612287 chr19: 21950228-21950330 ZNF100 0.328529297
7.16E-05 0.00404126 chr1: 95007092-95007356 F3 0.328897709
0.003923792 0.0943921 chr12: 72070468-72074419 THAP2 0.328949319
0.000936046 0.045949726 chr13: 37633616-37633850 FAM48A 0.329201798
0 0 chr2: 136481506-136482840 R3HDM1 0.329264663 0.004476477
0.098672627 chr9: 66553673-66555928 RP11- 0.329390698 0.004136364
0.095871025 262H14.4 chr13: 41345120-41345309 MRPS31 0.329399968
0.001803178 0.071315614 chr17: 4994791-4999668 ZFP3 0.329822496
0.00706482 0.122091644 chr1: 151141461-151142773 SCNM1 0.330275788
0.004023788 0.095037797 chr11: 32623824-32627808 EIF3M 0.330560474
0.007052809 0.122091644 chr8: 42029046-42029191 AP3M2 0.330606328
0.005212564 0.107708532 chr11: 64338450-64340347 SLC22A11
0.330712435 0.003990159 0.094844827 chr3: 32814948-32815367 CNOT10
0.330830953 0 0 chrX: 15682840-15683154 TMEM27 0.330831688
0.006114174 0.116162907 chr19: 36909393-36909558 ZFP82 0.330854448
0.000308635 0.016634253 chr14: 23240642-23241007 OXA1L 0.330898021
0.009077491 0.137166781 chr7: 64291828-64294054 ZNF138 0.33092203
0.004247302 0.096531516 chr14: 30661071-30661104 PRKD1 0.331146193
0.007424771 0.125564356 chr9: 100777645-100778225 ANP32B
0.331404852 0.008878 0.136076888 chr6: 10419650-10419892 TFAP2A
0.331452981 0.00775069 0.128531382 chr15: 23334999-23335196
AC091565.1 0.331545817 0.002559555 0.077611339 chr17:
58156056-58156292 HEATR6 0.331671707 0.00624891 0.116920758 chr11:
73964536-73965748 PPME1 0.33178239 0.011463933 0.153440983 chr19:
56347701-56348128 NLRP11 0.332151069 0.003966634 0.094764506 chr3:
64009480-64009658 PSMD6 0.332227431 0.004735818 0.101554491 chr15:
40331293-40331389 SRP14 0.332257211 0.009745137 0.142230949 chr15:
29409264-29410518 APBA2 0.332585829 0.00820806 0.132028532 chr10:
60588520-60591195 BICC1 0.332588003 0.005814869 0.11307866 chr16:
47177489-47177908 NETO2 0.33260473 0.002989626 0.083076103 chr10:
124713530-124713919 C10orf88 0.332876872 0.002993704 0.083076103
chr9: 127951840-127952218 PPP6C 0.332984853 0.003994731 0.094844827
chr1: 151735802-151736040 MRPL9 0.333136616 0.004195675 0.096098418
chr4: 120325655-120326749 AC110373.1 0.333522527 0.004232896
0.096464363 chr1: 152020297-152020383 S100A11 0.333566613
0.007853817 0.129133025 chrX: 24094838-24096088 EIF2S3 0.333582575
0.003071993 0.083904667 chr2: 207582984-207583120 DYTN 0.333890074
0.014367499 0.165520063 chr4: 146048677-146050331 ABCE1 0.333925697
0.003089387 0.084000815 chr2: 109492543-109493034 CCDC138
0.333976981 0.004349929 0.09789861 chr2: 231989685-231989832 HTR2B
0.334198112 0.004153272 0.095871025 chr11: 59436353-59436471 PATL1
0.334333206 0.007983468 0.12969294 chr11: 58384668-58388515 ZFP91
0.334555856 0 0 chr12: 120315052-120315095 CIT 0.334566849
0.012110335 0.155429477 chr9: 97090889-97090926 FAM22F 0.334602902
0.008513342 0.133361292 chr8: 103136797-103137135 NCALD 0.334783433
0 0 chr2: 99797169-99797521 MITD1 0.33494044 0.001482186
0.063564631 chr5: 140579182-140582618 PCDHB11 0.335046305
0.003710523 0.091703214 chr11: 66610639-66610987 C11orf80
0.335296837 0.003954429 0.094764506 chr12: 93894951-93897545 MRPL42
0.335324039 0.002410305 0.076804143 chr20: 21695108-21696620 PAX1
0.335448884 0.007190531 0.123441982 chr5: 134735438-134735604 H2AFY
0.335582907 0.007328985 0.124979581 chr1: 235611984-235612283 TBCE
0.335596516 0.003395192 0.086368012 chr19: 51538050-51538486 KLK12
0.335737191 0.00967498 0.142148692 chr18: 12884071-12884337 PTPN2
0.336004992 0.002423347 0.07683164 chr9: 19102521-19103117 HAUS6
0.336050358 0.00392889 0.0943921 chr16: 4322658-4323001 TFAP4
0.336101155 0.005641999 0.111386545 chr6: 32938355-32938493 HLA-DMA
0.336336244 0.01336062 0.16167151 chr6: 108508504-108510013 NR2E1
0.336437613 0.012157358 0.155429477 chr12: 6756489-6756626 ACRBP
0.336450652 0.009063847 0.137166781 chr11: 3400267-3400448 ZNF195
0.336605687 0.002843888 0.081237547 chr1: 25558934-25558993 SYF2
0.336667727 0.004644165 0.10077894 chr7: 16872879-16873057 AGR2
0.336738631 2.81E-05 0.001591309 chr12: 118405880-118406788 KSR2
0.336775902 0.007835265 0.129133025 chr19: 56988640-56988770 ZNF667
0.336884962 0.004098152 0.09575366 chr15: 83209176-83209208 RPS17L
0.336885484 0.003539674 0.08867737 chr10: 5498550-5500426 NET1
0.33716755 0.005108136 0.10615454 chr17: 50237283-50237377 CA10
0.337244385 0.008810051 0.135263703 chr4: 159825617-159829201 FNIP2
0.33761486 0.01001205 0.143216183 chr5: 159855608-159855748 PTTG1
0.337619827 0.012232275 0.155522345 chr14: 36982316-36982990 SFTA3
0.337685044 0.009064788 0.137166781 chr9: 140194082-140196703 NRARP
0.337748136 0.00700953 0.121921113 chr9: 104499562-104500862 GRIN3A
0.337777935 0.003309214 0.085620014 chr9: 125084818-125085743 MRRF
0.338049105 0.001250772 0.056511886 chr3: 167196633-167196792
SERPINI2 0.338488624 0.002335643 0.075350427 chr5:
98134164-98134347 RGMB 0.338500085 0 0 chr17: 6920575-6920844
AC040977.1 0.33861797 0.005612306 0.111134243 chr5:
154393314-154397692 KIF4B 0.33863313 0.006124103 0.116167412 chr1:
145440852-145442635 TXNIP 0.33868063 0.009449784 0.140634887 chr2:
113332423-113334673 POLR1B 0.338711651 0.005564022 0.110932307
chr5: 1886975-1887350 IRX4 0.338712821 0.002923933 0.082464901
chr2: 74729793-74732192 LBX2 0.338737246 0.010063139 0.14338159
chr3: 138663065-138665982 FOXL2 0.33877365 0.005017129 0.104742652
chr9: 88897292-88897676 ISCA1 0.339022749 0.006559848 0.1185295
chr10: 98273267-98273675 TLL2 0.339042421 0.003673076 0.091389151
chr2: 30862982-30867091 LCLAT1 0.339179902 0.006299765 0.116920758
chr3: 197682620-197683481 RPL35A 0.33923522 0.002247057 0.074896868
chr5: 140571941-140575215 PCDHB10 0.339319919 0.004991115
0.104560114 chr6: 3982908-3984372 AL138831.1 0.339526883
0.002639458 0.078334109 chr5: 171221568-171221602 C5orf50
0.339540771 0.004766959 0.101816018 chr4: 76911848-76912115 SDAD1
0.339847696 0.004162516 0.095871025 chr1: 92852567-92853730 RPAP2
0.340299513 0.00346415 0.087293121 chr17: 45899031-45899200 OSBPL7
0.34043401 0 0 chr16: 81110740-81110818 C16orf46 0.340560273
0.00461508 0.10049394 chr19: 55325296-55325972 KIR2DL4 0.340589063
0.002577114 0.077883735 chr5: 114598408-114598569 PGGT1B
0.340742067 0.003243526 0.085503862 chr6: 37225338-37225931 TMEM217
0.34102065 0.005320913 0.109004718 chr9: 131456919-131458679 SET
0.34104979 0.00334917 0.086040971 chr7: 130144779-130146133 MEST
0.341209576 0.002501724 0.076926292 chr1: 32798617-32799236 HDAC1
0.341243395 0.008437076 0.133216661 chr7: 117068123-117068177 ASZ1
0.341268169 0.018375867 0.183687882 chr1: 166818174-166825581 POGK
0.341341081 0.002180119 0.074896868 chr3: 169801692-169803191
GPR160 0.341411568 0 0 chr1: 173793699-173793858 CENPL 0.341600458
0.004386422 0.098116492 chr9: 37356831-37358146 ZCCHC7 0.341832318
0.002878016 0.081933244 chr6: 153452258-153452384 RGS17 0.341997405
0.007479401 0.126251813 chr19: 2877270-2878501 ZNF556 0.342151748
0.009710946 0.142148692 chr6: 150292504-150294844 ULBP1 0.342179031
0.007550635 0.126866028 chr1: 25824754-25826700 TMEM57 0.342284881
0.004046878 0.095335211 chr13: 26594025-26599989 ATP8A2 0.342473022
0.004835519 0.102307014 chr19: 12551725-12551926 ZNF443 0.342588553
0.00297085 0.083014679 chr1: 146253037-146253110 WI2- 0.342683663
0.012131595 0.155429477 3658N16.1 chr16: 18473011-18473188 RP11-
0.342756738 0.007019189 0.121921113 1212A22.4 chr6:
74233169-74233520 EEF1A1 0.342860281 0.003454471 0.087293121 chr2:
102003478-102004057 CREG2 0.342980433 0.007909977 0.129431455 chr5:
113831591-113832321 KCNN2 0.343097059 0.004322128 0.097640305
chr22: 24125597-24126503 MMP11 0.343244705 0.006555426 0.1185295
chr22: 38878500-38879452 KDELR3 0.343585262 0.005483917 0.109968839
chr14: 64108016-64108125 WDR89 0.343869473 0.002621089 0.078272928
chr14: 20825209-20826063 PARP2 0.34415271 0.009261923 0.139028346
chr8: 42229080-42229326 POLB 0.344522366 0.008229294 0.132039458
chr12: 110318076-110318293 GLTP 0.344549419 0.004690493 0.101059823
chr11: 114320567-114321001 REXO2 0.344608407 0.007037485
0.122083904 chr11: 132204939-132206716 NTM 0.344711378 0.005128034
0.106446266 chr19: 58513763-58514717 ZNF606 0.344730774 0.003193862
0.085052362 chr10: 12291579-12292588 CDC123 0.344789304 0.005742969
0.112400084
chr1: 40758116-40759856 ZMPSTE24 0.345388616 0.00276453 0.080210303
chr12: 53873189-53874945 PCBP2 0.345510005 0.00245255 0.07690982
chr11: 4673715-4676718 OR51E1 0.345933376 0.003329808 0.085908111
chr1: 43727512-43727589 EBNA1BP2 0.346047624 0.002367912
0.075986532 chr12: 104359293-104359486 C12orf73 0.346225796
0.003975695 0.094764506 chr3: 52029746-52029958 RPL29 0.346304272 0
0 chr19: 34302695-34306668 KCTD15 0.346487607 0.007147226
0.123047454 chr12: 102224336-102224716 GNPTAB 0.346582993
0.002656535 0.078584121 chr1: 186282812-186283694 PRG4 0.347040363
0.001203172 0.054952728 chr20: 57485737-57486247 GNAS 0.347157354
0.011944047 0.155429477 chr5: 72875701-72877794 UTP15 0.347177955 0
0 chr19: 1652298-1652326 TCF3 0.347341283 0.003229855 0.085267223
chr8: 17104183-17104387 CNOT7 0.347410862 0.003680922 0.091459073
chr4: 88312012-88312538 HSD17B11 0.347520476 0.008454701
0.133216661 chr16: 67418772-67419106 LRRC36 0.347808564 0.005934616
0.114006188 chr12: 70747608-70748773 CNOT2 0.348186738 0.001273157
0.057173139 chr1: 52552383-52556388 BTF3L4 0.348370433 0.002680623
0.078783422 chr17: 36294031-36294915 TBC1D3F 0.34873563 0.002667289
0.078646054 chr22: 31363051-31364284 MORC2 0.348951739 0.003750785
0.092052993 chr15: 52356098-52358462 MAPK6 0.34926453 0.007410428
0.125555604 chr10: 50970284-50970425 OGDHL 0.349324408 0.00510169
0.106142027 chr6: 7417563-7418270 RIOK1 0.349666416 0.007217973
0.12367929 chr12: 69783926-69784576 YEATS4 0.350000562 0.008141607
0.131445347 chr13: 100622380-100624163 ZIC5 0.35012692 0.008295958
0.132523738 chr9: 95244574-95244788 ASPN 0.350256133 0.003759281
0.092052993 chr8: 101965496-101965616 YWHAZ 0.350510592 0.005746975
0.112400084 chr20: 55840760-55841685 BMP7 0.350559373 0.002260921
0.074896868 chr2: 47614696-47614740 EPCAM 0.350697329 0.005088462
0.105988221 chr9: 139304779-139305061 SDCCAG3 0.350723691
0.003054233 0.083821279 chr16: 332614-333003 ARHGDIG 0.350753346
0.010006296 0.143216183 chr19: 19007369-19007488 LASS1 0.351329035
0.010345517 0.145135442 chr9: 33917015-33920402 UBE2R2 0.351623699
0.003205954 0.085084821 chr10: 33625122-33625190 NRP1 0.351650511
0.000150014 0.008357973 chr4: 70079719-70080449 UGT2B11 0.351862854
0.007741352 0.128531382 chr7: 99679923-99680171 ZNF3 0.352255056
0.010014015 0.143216183 chr17: 40169357-40169715 DNAJC7 0.352324455
0.001535738 0.065020053 chr6: 88376735-88377169 ORC3 0.352508512 0
0 chr1: 2564304-2564481 MMEL1 0.352661402 0 0 chr17:
74944721-74946465 MGAT5B 0.352666207 0.004035915 0.095200415 chr19:
52511393-52511483 ZNF615 0.352758492 0.000854457 0.042519208 chr12:
54678041-54680872 HNRNPA1 0.352793166 0 0 chr21: 45079266-45079374
HSF2BP 0.352847214 0.003836372 0.093530226 chr6: 76425100-76427997
SENP6 0.352949584 0.002051473 0.074404864 chr8: 86129188-86129387
E2F5 0.352950312 0.002863213 0.081639789 chr16: 19716437-19716880
C16orf62 0.353016377 0 0 chr1: 148025760-148025863 NBPF14
0.353092408 0.004067093 0.09564239 chr7: 155255065-155257526 EN2
0.353146057 0.007860271 0.129133025 chr14: 70826235-70826444 COX16
0.353343863 0.002633087 0.078272928 chr5: 140588268-140591696
PCDHB12 0.353452742 0.002137676 0.074896868 chr6: 97345541-97345757
NDUFAF4 0.353576318 0.000829729 0.041516184 chr19:
21560190-21562104 ZNF738 0.3536571 0.005514988 0.110317975 chr5:
140557370-140560081 PCDHB8 0.353698505 0.00831499 0.13259453 chr4:
55161291-55161439 FIP1L1 0.353817549 0.004681278 0.10098106 chr17:
79771349-79771889 GCGR 0.354035638 0.005445589 0.109898029 chr19:
52793318-52795977 ZNF766 0.354073875 0.002226165 0.074896868 chr1:
63788729-63790797 FOXD3 0.354149363 0.005405168 0.109447113 chr1:
147954634-147955419 PPIAL4A 0.354222847 0.002675456 0.078759014
chr12: 122496997-122499948 BCL7A 0.354825754 0.002231741
0.074896868 chr9: 123605014-123605229 PSMD5 0.355144141 0 0 chr2:
233412778-233415226 TIGD1 0.355197399 0.004022874 0.095037797
chr22: 49246569-49246724 FAM19A5 0.355373328 0.00336784 0.086049007
chr17: 41154888-41154956 RPL27 0.355442918 0.002963896 0.083014679
chr12: 123741359-123742506 C12orf65 0.355530218 0.013002282
0.159180228 chr6: 31937586-31940069 DOM3Z 0.355568549 0.006009592
0.114897067 chr17: 5322673-5323000 NUP88 0.355910655 0.002129205
0.074896868 chr8: 26227649-26230196 PPP2R2A 0.356005328 0.00272447
0.079641256 chr2: 74734702-74735707 PCGF1 0.356137025 0.006485052
0.118025771 chr10: 70968355-70968855 SUPV3L1 0.35616511 0 0 chrX:
70519791-70521018 NONO 0.35629128 0.003965269 0.094764506 chr2:
44547337-44548633 SLC3A1 0.356342942 0.013472925 0.162218034 chr7:
87536502-87538856 DBF4 0.356363925 0.006137741 0.116167412 chr19:
37019120-37019562 ZNF260 0.356458224 0.002725493 0.079641256 chr1:
149899617-149900236 SF3B4 0.356570693 0.002827474 0.081130196 chr4:
83822235-83822319 SEC31A 0.35704326 0.003360274 0.086049007 chr8:
19615360-19615540 CSGALNACT1 0.357581398 0 0 chr6:
44221225-44221620 HSP90AB1 0.357638149 0.004764199 0.101816018
chr8: 54934622-54935089 TCEA1 0.357638989 0.003470001 0.087293121
chr4: 13485699-13485989 RAB28 0.358225721 0.00029466 0.015975864
chr10: 61665879-61666414 CCDC6 0.358410884 0.004770436 0.101816018
chr15: 82939013-82939159 RP13-98N21.1 0.358524403 0.003390575
0.086368012 chr5: 170837530-170838141 NPM1 0.358661212 0.003112663
0.084283617 chr5: 138665033-138667360 MATR3 0.358905176 0 0 chr1:
150443036-150449042 RPRD2 0.358931012 0.001044122 0.049906291
chr19: 39303481-39303740 LGALS4 0.359501829 0.002800501 0.080691396
chr7: 143002032-143004789 CASP2 0.359779958 0.0052784 0.108821635
chr14: 64804615-64805317 AL161756.1 0.360196944 0.001852672
0.072262867 chr17: 44833167-44834830 NSF 0.360685738 0.004164634
0.095871025 chr11: 114284677-114284925 RBM7 0.360737625 0 0 chr2:
180725827-180726232 ZNF385B 0.360753689 0.000458772 0.024364569
chr19: 51587392-51587502 KLK14 0.361259901 0.009570729 0.141580566
chr19: 52868950-52870375 ZNF610 0.361291389 0.001739732 0.070219452
chr14: 21737456-21737638 HNRNPC 0.361477927 0.002287559 0.074896868
chr11: 117155801-117157161 RNF214 0.361847621 0.00250308
0.076926292 chr13: 79979835-79980612 RBM26 0.36206404 0.00677961
0.120633891 chr5: 32601110-32604185 SUB1 0.362303909 0 0 chr6:
53787432-53788919 LRRC1 0.362759243 0.001706266 0.069486359 chr11:
22644078-22647387 FANCF 0.363489573 0 0 chr20: 52844491-52844591
PFDN4 0.363560498 0 0 chr6: 30613671-30614600 ATAT1 0.363580156
0.003898538 0.094210495 chr16: 70605575-70608820 SF3B3 0.363659853
0.008588833 0.134075072 chr16: 3355211-3355645 TIGD7 0.363725026 0
0 chr1: 161135146-161135513 USP21 0.363771581 0.002323203
0.075082439 chr8: 101733618-101735037 PABPC1 0.364174471
0.002118261 0.074896868 chr1: 151688094-151689290 CELF3 0.364376964
0.002952999 0.083014679 chr9: 133376362-133376661 ASS1 0.364697462
0.00725575 0.124092447 chr12: 3048476-3050306 TULP3 0.364753258
0.006132467 0.116167412 chr4: 111120255-111120355 ELOVL6
0.364868424 0.003051244 0.083821279 chr9: 19378705-19380252 RPS6
0.365038972 0.002300966 0.074896868 chr10: 121302101-121302220
RGS10 0.365192 0.002278591 0.074896868 chr16: 277240-279462 LUC7L
0.365306003 0.003898555 0.094210495 chr19: 24309055-24312643 ZNF254
0.365391007 0.00247424 0.076926292 chrX: 152241317-152243401
AC152006.1 0.365477178 0.002089412 0.074557938 chr1:
116609639-116612675 SLC22A15 0.365617395 0.005365482 0.109252525
chr15: 69113036-69113236 ANP32A 0.366537633 0.002497996 0.076926292
chr11: 6463716-6463847 HPX 0.36658236 0.003082241 0.084000815
chr17: 4269565-4269969 UBE2G1 0.366624907 0 0 chr17:
30228554-30228731 UTP6 0.366824192 0.003624029 0.09052543 chr5:
178157556-178157703 ZNF354A 0.367356176 0.002058499 0.074404864
chr14: 21464685-21465189 METTL17 0.367400305 0.002197521
0.074896868 chr1: 144828540-144830302 NBPF9 0.3679992 0.000828298
0.041516184 chr16: 3284635-3285456 ZNF200 0.368145566 0.004814693
0.102159863 chr19: 33078158-33078322 PDCD5 0.368297261 0.004138572
0.095871025 chr1: 17766040-17766220 RCC2 0.36830465 0.006298625
0.116920758 chr22: 31740317-31742218 PATZ1 0.368414717 0 0 chr4:
96075698-96079599 BMPR1B 0.368570648 0 0 chr2: 190339938-190340291
WDR75 0.368575508 0.001803079 0.071315614 chr15: 52970768-52970820
KIAA1370 0.369520608 0.001991434 0.07433842 chr3: 62359972-62359999
FEZF2 0.370011496 0.006297319 0.116920758 chr14: 36789665-36789882
MBIP 0.370390986 0.002395341 0.076596085 chr9: 131303380-131304567
GLE1 0.370432615 0.001207478 0.054952728 chr19: 36726560-36729673
ZNF146 0.37076253 0.001797055 0.071315614 chr11: 76731317-76737841
ACER3 0.371547935 0.002473745 0.076926292 chr5: 44816544-44820530
MRPS30 0.372171618 0.001169204 0.054060041 chr20: 50418817-50419014
SALL4 0.372219721 0.002515478 0.077005838 chr2: 175113179-175113426
OLA1 0.372322556 0 0 chr11: 43876693-43878167 HSD17B12 0.372729256
0.002281533 0.074896868 chr6: 111214678-111216916 AMD1 0.372775014
0 0 chr2: 44999174-44999731 CAMKMT 0.372782137 0.002908212
0.08228265 chr17: 30380284-30380517 LRRC37B 0.374033979 0.002518387
0.077005838 chr14: 91883974-91884152 CCDC88C 0.374642963
0.000670737 0.034807417 chr1: 85514078-85514182 MCOLN3 0.374684625
0.003969808 0.094764506 chr11: 26744853-26744974 SLC5A12
0.375189064 0.010525668 0.146272153 chr3: 52089865-52090566 DUSP7
0.375203447 0.002453789 0.07690982 chr11: 102340904-102341115
TMEM123 0.375721711 0.00219416 0.074896868 chr6: 27368071-27371683
ZNF391 0.375903341 0 0 chr7: 19156293-19157295 TWIST1 0.376075851
0.000868692 0.043055081 chrX: 129063311-129063737 UTP14A
0.376243265 0.002051346 0.074404864 chr21: 18965469-18965897 CXADR
0.377652362 0 0 chr5: 68665483-68665840 TAF9 0.37769513 0.00220028
0.074896868 chr7: 149470196-149470568 ZNF467 0.377842565
0.002987109 0.083076103 chr14: 89088611-89088615 ZC3H14 0.377843839
0 0 chr6: 137112847-137113656 MAP3K5 0.378372715 0.003924303
0.0943921 chr1: 155707947-155708803 DAP3 0.378584615 0 0 chr12:
118500157-118500235 WSB2 0.378701761 0.003285179 0.085620014 chr12:
122985186-122985518 ZCCHC8 0.37906625 0 0 chr20: 13797763-13799067
C20orf7 0.379646265 0.002733521 0.079693317 chr20:
20693017-20693266 RALGAPA2 0.379953096 0.000392922 0.02099011
chr17: 27940371-27941779 ANKRD13B 0.379965854 0 0 chr2:
24991089-24993571 NCOA1 0.380049681 0.003108189 0.084283617 chr1:
2706067-2706280 TTC34 0.380131608 0.00112532 0.053024689 chr11:
61136068-61136683 TMEM138 0.380382477 0.002431464 0.07683164 chr5:
72801016-72801460 BTF3 0.380632257 0.004553657 0.099768482 chr12:
26277650-26278060 BHLHE41 0.380649557 0.000869967 0.043055081
chr11: 77348634-77348850 CLNS1A 0.381389378 0 0 chr11:
64940653-64940715 SPDYC 0.381489194 0.001862618 0.072287892 chr1:
169555466-169555826 F5 0.382149137 0 0 chr1: 113212613-113214241
CAPZA1 0.382444099 0 0 chr11: 118888070-118889401 RPS25 0.38247485
0 0 chr6: 119228566-119230332 ASF1A 0.382887636 0 0 chr9:
96082648-96082854 WNK2 0.383066155 0.002147218 0.074896868 chr16:
48419114-48419361 SIAH1 0.38346374 0 0 chr6: 117252493-117253326
RFX6 0.383666724 0.003137472 0.08454882 chr5: 140890513-140892546
PCDHGA1 0.384828032 0 0 chr1: 203821268-203823252 ZC3H11A
0.385182686 0 0 chr12: 57125273-57125412 NACA 0.386358061
0.002030959 0.074404864 chr19: 11849631-11849824 ZNF823 0.386599542
0 0 chr22: 41255552-41258130 DNAJB7 0.386599867 0 0 chr9:
86595417-86595569 HNRNPK 0.38694272 0 0 chr12: 21391912-21392180
SLCO1B1 0.38730007 0 0 chr4: 165878099-165880274 C4orf39
0.387654409 0 0 chr13: 53216540-53217919 HNRNPA1L2 0.387659039
0.003340795 0.085969228 chr7: 16921567-16921611 AGR3 0.387702629
0.003578066 0.089515727 chr10: 27035261-27035727 PDSS1 0.388612797
0.002981744 0.083076103 chr12: 15114470-15114662 ARHGDIB
0.388654077 0 0 chr9: 74525549-74525847 FAM108B1 0.389098607 0 0
chr4: 77996624-77997158 CCNI 0.389315949 0 0 chr22:
29137756-29138410 CHEK2 0.389761154 0.00049489 0.026054161 chr4:
69696317-69696914 UGT2B10 0.390049265 0.00315215 0.08468855 chr4:
44700560-44702943 GUF1 0.390286785 0.001037899 0.049739741 chr4:
169931098-169931426 CBR4 0.390480296 0.002223282 0.074896868 chr1:
46158875-46160115 TMEM69 0.390570946 0.000653249 0.033997013 chr19:
11494768-11495018 EPOR 0.390666769 0.001169718 0.054060041 chr6:
32151657-32152101 AGER 0.39120754 0.002536025 0.077155474 chrX:
51238802-51239448 NUDT11 0.392382255 0 0 chr11: 1481729-1483919
BRSK2 0.392392838 0.001425388 0.061936163 chr10: 35927176-35930362
FZD8 0.392659985 0.002373224 0.07602269 chr5: 34924951-34926101
BRIX1 0.392764346 0.000257339 0.014078459 chr11:
108810972-108811657 DDX10 0.393686876 0 0 chr6: 151422661-151423023
MTHFD1L 0.393780109 0 0 chr5: 179498455-179499118 RNF130 0.39413346
0.002300383 0.074896868 chr2: 207653542-207657233 FASTKD2
0.395080106 0.002995917 0.083076103 chr1: 32801547-32801980
MARCKSL1 0.395222571 0 0 chr15: 58073773-58074960 GRINL1A
0.395317713 0 0 chr5: 150080493-150080669 RBM22 0.395392528
0.00249879 0.076926292 chr11: 58345458-58345693 LPXN 0.395428297
0.003088638 0.084000815 chr1: 167757056-167761156 MPZL1 0.395807291
0 0 chr1: 154531383-154531504 UBE2Q1 0.395931922 0 0 chr21:
27107163-27107984 ATP5J 0.395993559 0.001203617 0.054952728 chr1:
84963111-84963473 RPF1 0.396095665 0 0 chr14: 20925149-20925933
APEX1 0.396178148 0.001190996 0.05490369 chr6: 116914142-116918838
RWDD1 0.396503437 0.002228124 0.074896868 chr9: 33798853-33799230
PRSS3 0.397409769 0 0 chr9: 74597572-74600970 C9orf85 0.397495381 0
0 chr11: 62507447-62507756 TTC9C 0.397920759 0 0 chr6:
47009926-47010099 GPR110 0.397964341 0.002809976 0.080755689 chr1:
236385090-236385165 GPR137B 0.398121433 0.002838645 0.081237547
chr6: 107979410-107981357 SOBP 0.39849222 0 0 chr1:
151220338-151222012 PIP5K1A 0.398670482 0.001578429 0.066031038
chr12: 21242841-21243179 RP11-545J16.1 0.398687934 0.002064621
0.074404864 chr1: 154243356-154243986 UBAP2L 0.398763956
0.001640837 0.067674286 chr2: 9613044-9613230 CPSF3 0.398839677
0.000818676 0.04119004 chr6: 28097207-28097860 ZSCAN16 0.399313964
0 0 chr5: 68849396-68853931 OCLN 0.399353915 0 0 chr1:
183567145-183567381 SMG7 0.399418476 0 0 chr12: 50492729-50494495
SMARCD1 0.399921615 0 0 chr10: 33171620-33171802 C10orf68
0.39996233 0 0 chr7: 23571407-23571660 TRA2A 0.400855902
0.001909912 0.07290082 chr1: 2520848-2522908 C1orf93 0.401674406
0.000832687 0.041549723 chr21: 33103975-33104431 SCAF4 0.401930251
0.00367158 0.091389151 chr6: 30530165-30531500 PRR3 0.402082178
0.003156645 0.08468855 chr2: 223520734-223521056 FARSB 0.402157653
0.001309609 0.058443307 chr12: 96437066-96437298 LTA4H 0.402185173
0 0 chr5: 140041763-140042064 IK 0.402703343 0.001774987
0.071167982 chr1: 155248165-155248282 CLK2 0.40304566 0.002943221
0.082880196 chr10: 71871273-71872032 H2AFY2 0.403191879 0 0 chr13:
103491900-103493885 BIVM 0.40403719 0.000414281 0.022066226 chr1:
228353174-228353213 C1orf148 0.404051637 0.000953353 0.046515259
chr2: 42719976-42721237 KCNG3 0.404235536 0.0011298 0.053024689
chr1: 54879028-54879152 SSBP3 0.404739966 0.001387273 0.060862399
chr3: 195310748-195311076 APOD 0.405410563 0 0 chr9:
129458572-129463311 LMX1B 0.406246618 0.002026027 0.074404864
chr11: 93583577-93583697 C11orf90 0.406962716 0.002608771
0.078272928 chr12: 56693943-56694176 CS 0.407050318 0 0 chr22:
44258093-44258398 SULT4A1 0.407538876 0 0 chr19: 14201749-14201848
SAMD1 0.407614144 0 0 chr17: 44632896-44633016 LRRC37A2 0.40823187
0.00107377 0.051188688 chr7: 33148832-33149013 RP9 0.408861449 0 0
chr19: 20046830-20046860 ZNF93 0.409274151 0 0 chr15:
77241410-77242601 RCN2 0.409441008 0.001415528 0.061655257 chr1:
26233278-26233482 STMN1 0.409501544 0 0
chr1: 222886085-222886552 AIDA 0.410481766 0.00279499 0.080691396
chr13: 100637576-100639018 ZIC2 0.410515198 0.001274851 0.057173139
chr2: 181940922-181941312 UBE2E3 0.410818774 0.002071907
0.074404864 chr8: 97273728-97273838 MTERFD1 0.411514119 0 0 chr6:
80751835-80752244 TTK 0.412567895 0.000782933 0.039721802 chr11:
49229843-49230222 FOLH1 0.412864835 0.000915002 0.045038408 chr11:
18127453-18127638 SAAL1 0.412967343 0.001716101 0.069576817 chr2:
74718607-74722013 TTC31 0.413386439 0.002320775 0.075082439 chr2:
172952730-172954405 DLX1 0.413626042 0 0 chr1: 156051335-156051789
MEX3A 0.414113678 0 0 chr20: 45985400-45985567 ZMYND8 0.414360157
0.003386848 0.086368012 chr6: 20490398-20493945 E2F3 0.414889711 0
0 chr9: 17502548-17503921 CNTLN 0.415096245 0 0 chr11:
125933120-125933230 CDON 0.415241654 0.003399941 0.086368012 chr16:
1374730-1377019 UBE2I 0.415614971 0.000805294 0.04062931 chr4:
85418711-85419603 NKX6-1 0.415770608 0.002969533 0.083014679 chr1:
2345035-2345236 PEX10 0.415818061 0.00226998 0.074896868 chr13:
37583320-37583750 EXOSC8 0.41616237 0 0 chr6: 114332294-114332472
HDAC2 0.41634724 0 0 chr11: 94730187-94732682 KDM4D 0.416396892 0 0
chr7: 96639107-96640351 DLX6 0.416500311 0 0 chr1:
43316593-43318148 ZNF691 0.417052551 0 0 chr6: 30620387-30620987
C6orf136 0.417479864 0 0 chr1: 38455541-38456593 SF3A3 0.419671206
0 0 chr16: 3450944-3451030 ZNF434 0.421275822 0 0 chr2:
27886195-27886676 SUPT7L 0.421878368 0 0 chr3: 131221573-131221827
MRPL3 0.422205914 0.004302763 0.097323884 chr6: 117890782-117891021
DCBLD1 0.422518501 0 0 chr6: 37298819-37300746 TBC1D22B 0.422672614
0 0 chr19: 52531494-52531680 ZNF614 0.422808785 0.001307515
0.058443307 chr12: 76478346-76478813 NAP1L1 0.423706864 0 0 chr6:
110797724-110797844 SLC22A16 0.424337101 0 0 chr17:
38290531-38293040 MSL1 0.425415614 0 0 chr2: 71192087-71192555
ATP6V1B1 0.425997989 0 0 chr1: 236645566-236648026 EDARADD
0.426385524 0 0 chr1: 90398625-90402170 LRRC8D 0.4277395 0 0 chr15:
34880591-34880704 GOLGA8A 0.428326543 0.001214634 0.055015953
chr17: 27277912-27278789 PHF12 0.428389454 0.001210213 0.054952728
chr7: 50632981-50633154 DDC 0.428397647 0 0 chr10:
122348814-122349367 PPAPDC1A 0.428573634 0.002188707 0.074896868
chr12: 54428061-54429145 HOXC5 0.429414056 0.001786691 0.071315614
chr3: 63849179-63849579 THOC7 0.429484227 0 0 chr17:
57351011-57353322 GDPD1 0.430283967 0 0 chr19: 11529921-11530018
RGL3 0.432861793 7.75E-05 0.004357466 chr12: 54423414-54424607
HOXC6 0.432933362 0.001968332 0.074231845 chr6: 107372260-107372546
C6orf203 0.433507583 0.000780773 0.039721802 chr17:
27169675-27169841 C17orf63 0.43537005 0 0 chr12: 2113366-2113701
DCP1B 0.438106424 0.002757557 0.080136814 chr20: 62168437-62168723
PTK6 0.438444953 0.002433076 0.07683164 chr20: 524315-524482
CSNK2A1 0.438596671 0 0 chr2: 40006253-40006407 THUMPD2 0.438989821
0 0 chr1: 38061359-38061540 GNL2 0.439023194 0 0 chr7:
40899914-40900362 C7orf10 0.439295183 0.001314219 0.058505314
chr12: 54448633-54449814 HOXC4 0.440488904 0.00162294 0.067166971
chr2: 86422460-86422893 IMMT 0.440753615 0.000251254 0.013818534
chr4: 147442769-147443123 SLC10A7 0.441806672 0.001164603
0.054060041 chr1: 145368440-145370303 NBPF10 0.441846603 0 0 chr6:
46669594-46672056 TDRD6 0.442466815 0 0 chr5: 136933886-136934068
SPOCK1 0.443225182 0 0 chr4: 39529418-39529931 UGDH 0.444185722 0 0
chr8: 145979576-145981802 ZNF251 0.445163073 0.001145009 0.05346221
chr11: 381668-382116 B4GALNT4 0.445270209 0 0 chr5:
68737358-68740157 MARVELD2 0.446183422 0.001432367 0.06194304 chr1:
150325308-150325671 PRPF3 0.447239122 0 0 chr3: 53845139-53846490
CACNA1D 0.448853672 0 0 chr9: 126030714-126030855 STRBP 0.449208753
0 0 chrX: 109683117-109683461 AMMECR1 0.449831614 0.003696425
0.091617209 chr5: 74072428-74072737 NSA2 0.450170336 0.000888381
0.043846937 chr19: 19654489-19657468 CILP2 0.451206343 0 0 chr22:
19770836-19771116 TBX1 0.45229799 0.00133281 0.059043466 chr16:
11945264-11945442 RSL1D1 0.453363354 0 0 chr12: 56509926-56509935
PA2G4 0.453629094 0.001682554 0.068829349 chr11: 18063910-18063973
TPH1 0.454146123 0.001759224 0.070831349 chr6: 111137010-111137161
CDK19 0.461218971 0 0 chr5: 11903928-11904155 CTNND2 0.46164781 0 0
chr9: 23825803-23826335 ELAVL2 0.461847559 0.001878907 0.072455602
chr5: 137910926-137911133 HSPA9 0.462177989 0 0 chr16:
15224943-15225458 PKD1P6 0.463922149 0 0 chr10: 115991244-115992063
TDRD1 0.464073889 0 0 chr11: 49059029-49059579 AC084851.1
0.464703457 0.000995607 0.048093643 chrX: 135962755-135962939 RBMX
0.467663273 0 0 chr15: 74005274-74006859 CD276 0.469036908
0.001399893 0.061268074 chr6: 76624529-76629254 MYO6 0.472241272 0
0 chr6: 105627707-105627870 POPDC3 0.474183404 0 0 chr1:
224517772-224518089 NVL 0.474352541 0.000217576 0.012048295 chr9:
93405033-93405386 DIRAS2 0.476231667 0 0 chr20: 1373477-1373806
FKBP1A 0.477529689 0 0 chr9: 131262345-131263239 ODF2 0.479887989 0
0 chr10: 124923335-124924886 BUB3 0.481360778 0.000709825
0.03641962 chr5: 133304136-133304478 C5orf15 0.481540922 0 0 chr1:
84855461-84855640 SAMD13 0.483533428 0 0 chr5: 79865972-79866307
ANKRD34B 0.48535555 0 0 chr3: 132004083-132004254 CPNE4 0.487204732
0 0 chr1: 40783259-40783488 COL9A2 0.488099327 0 0 chr6:
111346605-111347303 RPF2 0.488404844 0 0 chr12: 82152992-82153332
PPFIA2 0.488405043 0 0 chr1: 76076724-76076801 SLC44A5 0.48908972
0.00026347 0.014369004 chr11: 94965320-94965705 SESN3 0.490557941 0
0 chr5: 102611597-102614361 C5orf30 0.50386609 0 0 chr1:
166845396-166845564 TADA1 0.508490879 0 0 chr6: 28200339-28201260
ZNF193 0.511690319 0 0 chr4: 122617735-122618268 ANXA5 0.516661902
0 0 chr2: 203630168-203634480 FAM117B 0.517778257 0 0 chr15:
82554954-82555104 EFTUD1 0.51899271 0 0 chr6: 46703286-46703430
PLA2G7 0.519577791 0 0 chr6: 24785865-24786327 GMNN 0.522285573 0 0
chr3: 175520792-175523428 NAALADL2 0.531051532 0 0 chr1:
70587462-70589164 LRRC7 0.531438025 0 0 chr6: 38997880-38998301
DNAH8 0.533275843 0 0 chr1: 31769457-31769662 SNRNP40 0.533891931 0
0 chr3: 3886047-3889387 LRRN1 0.539082031 0 0 chr17:
4545517-4545589 ALOX15 0.542179201 0 0 chr18: 55143668-55158530
ONECUT2 0.543914583 0 0 chr18: 63547636-63552376 CDH7 0.547130694 0
0 chr11: 129728468-129729898 TMEM45B 0.551304803 0 0 chr17:
38821255-38821393 SMARCE1 0.554810297 0 0 chr6: 107436293-107436473
BEND3 0.555214105 0 0 chr1: 180991774-180992047 STX6 0.555781993
0.001806154 0.071315614 chr9: 114361882-114362135 PTGR1 0.556369465
0 0 chr3: 193855471-193856521 HES1 0.556473721 0 0 chr6:
38670746-38670917 GLO1 0.559523889 0 0 chr2: 71159896-71160576 VAX2
0.561327888 0 0 chr8: 136668468-136668965 KHDRBS3 0.563811465 0 0
chr9: 79634570-79635869 FOXB2 0.583315396 0 0 chr1:
31712340-31712401 NKAIN1 0.590810474 0 0 chr6: 107780193-107780768
PDSS2 0.595945426 0 0 chr2: 181780999-181782519 SCHLAP1 1 0 0 locus
pglobal qglobal prank padj chr12: 57180908-57181574 2.21E-06
0.002893994 0.000660684 0.001483863 chr10: 100995269-100995619
4.25E-06 0.003261046 0.000935969 0.000935969 chr9: 4585311-4587469
4.60E-06 0.003261046 0.001046083 0.001046083 chr12:
104234726-104234975 4.88E-06 0.003261046 0.001266311 0.001266311
chr1: 85358698-85358896 5.53E-06 0.003261046 0.001541596
0.001541596 chr7: 12692212-12693228 6.48E-06 0.003676617 0.00165171
0.00165171 chr1: 204328821-204329044 6.68E-06 0.003676889
0.001706767 0.001706767 chr22: 31674282-31676066 8.12E-06
0.004015199 0.001871937 0.001871937 chr16: 85121881-85127826
8.39E-06 0.004015199 0.001926994 0.001926994 chr11:
126310080-126310239 8.40E-06 0.004015199 0.001982051 0.001982051
chr2: 102855651-102856462 9.02E-06 0.004201028 0.002037108
0.002037108 chr2: 100759172-100759201 9.27E-06 0.004210011
0.002092165 0.002092165 chr3: 87039767-87040269 1.09E-05
0.004810345 0.002257336 0.002257336 chr10: 106058885-106059616
1.52E-05 0.00641619 0.002202279 0.002202279 chr18:
78005159-78005429 1.56E-05 0.006424942 0.00236745 0.00236745 chr5:
14692962-14699820 1.76E-05 0.007084909 0.002422507 0.002422507
chr11: 124955849-124959131 1.97E-05 0.007236461 0.002312393
0.002312393 chr11: 134134801-134135749 2.40E-05 0.008231158
0.002587678 0.002587678 chr12: 104159806-104160505 2.45E-05
0.008235358 0.002642735 0.002642735 chr13: 24462816-24463558
2.88E-05 0.009222872 0.002807906 0.002807906 chr15:
89738457-89745591 2.89E-05 0.009222872 0.003028134 0.003028134
chr16: 22295207-22297954 3.24E-05 0.009557199 0.002862963
0.002862963 chr6: 159185526-159185908 3.32E-05 0.009557199
0.002973077 0.002973077 chr2: 204399833-204400133 4.11E-05
0.010718571 0.003248362 0.003248362 chr21: 35987058-35987441
4.13E-05 0.010718571 0.003303419 0.003303419 chr2:
242089022-242089679 4.23E-05 0.01082872 0.003358476 0.003358476
chr1: 153603987-153604513 4.69E-05 0.011520023 0.00346859
0.00346859 chr9: 77502739-77503010 5.03E-05 0.012121545 0.003523647
0.003523647 chr5: 66458974-66465423 5.40E-05 0.012121545
0.003578704 0.003578704 chr12: 112247346-112247782 5.50E-05
0.012121545 0.003633761 0.003633761 chr20: 33460449-33460663
5.50E-05 0.012121545 0.003688818 0.003688818 chr16:
84695183-84701292 6.03E-05 0.012724535 0.004404559 0.004404559
chr5: 55218223-55218678 6.09E-05 0.012724535 0.00401916 0.00401916
chrX: 63615219-63615333 6.18E-05 0.012761283 0.004074217
0.004074217 chr16: 84538206-84538296 6.44E-05 0.013127093
0.004129274 0.004129274 chrX: 18671551-18671749 6.50E-05
0.013127093 0.004184331 0.004184331 chr10: 94050682-94050844
6.65E-05 0.0132686 0.004239388 0.004239388 chr18: 11908199-11908779
6.74E-05 0.013313983 0.004294445 0.004294445 chr3:
189839991-189840226 7.07E-05 0.013784792 0.0051203 0.0051203 chr1:
154321315-154323783 7.13E-05 0.013784792 0.004349502 0.004349502
chr4: 100009839-100009952 7.21E-05 0.013789835 0.004404559
0.004404559 chr2: 202028557-202029033 9.16E-05 0.016804159
0.004514673 0.004514673 chr11: 130272233-130273133 9.42E-05
0.016939391 0.00456973 0.00456973 chr4: 106924870-106925184
9.56E-05 0.017026472 0.005395584 0.005395584 chr17:
53809031-53809482 9.71E-05 0.017086351 0.004624787 0.004624787
chr18: 19102618-19102791 0.00010456 0.017905164 0.004734901
0.004734901 chr7: 128461852-128462186 0.000105283 0.017905164
0.004789958 0.004789958 chr4: 113206795-113207059 0.000110766
0.018214263 0.004900072 0.004900072 chr13: 111955337-111958084
0.000113277 0.018370082 0.005010186 0.005010186 chr7:
103086544-103086624 0.000118707 0.018912891 0.005615812 0.005615812
chr2: 199436579-199437305 0.000122153 0.019126366 0.0051203
0.0051203 chr7: 99526462-99527243 0.000124666 0.019242801
0.005175356 0.005175356 chr17: 1613360-1613651 0.000126503
0.019242801 0.005670869 0.005670869 chr11: 44640598-44641913
0.00013486 0.020077586 0.005340527 0.005340527 chr11:
134094990-134095348 0.000136153 0.020105287 0.005395584 0.005395584
chr1: 152297664-152297679 0.000144867 0.020358172 0.005560755
0.005560755 chr18: 8406106-8406859 0.000145 0.020358172 0.005615812
0.005615812 chr11: 74178676-74178774 0.000145712 0.020358172
0.005725926 0.005725926 chr17: 7951703-7952452 0.000150385
0.020596714 0.005780983 0.005780983 chr3: 49213037-49213918
0.000150553 0.020596714 0.00583604 0.00583604 chr2:
219696460-219696809 0.000150821 0.020596714 0.005891097 0.005891097
chr14: 23778024-23780968 0.000162326 0.021533748 0.005946154
0.005946154 chr8: 11182824-11182938 0.000166756 0.021533748
0.006331553 0.006331553 chr14: 77843278-77843396 0.000174114
0.021961395 0.007763035 0.007763035 chr8: 22926263-22926692
0.000198143 0.024649764 0.006221439 0.006221439 chr11:
118550247-118550399 0.000206789 0.025550394 0.006276496 0.006276496
chr8: 22471420-22474170 0.000215369 0.025749707 0.006331553
0.006331553 chr14: 76668033-76669134 0.000215491 0.025749707
0.00638661 0.00638661 chr7: 83277743-83278479 0.00021898
0.025995608 0.006441667 0.006441667 chr8: 109095151-109095913
0.000231367 0.027287785 0.006496724 0.006496724 chr6:
42931272-42931618 0.000243869 0.027410832 0.006661895 0.006661895
chr1: 24795475-24799466 0.00024945 0.027410832 0.006661895
0.006661895 chrX: 148713225-148713568 0.000251178 0.027410832
0.006772009 0.006772009 chr6: 52860046-52860176 0.00025189
0.027410832 0.008974288 0.008974288 chr11: 4903048-4904113
0.000252001 0.027410832 0.008809117 0.008809117 chr20:
45362394-45364965 0.000253538 0.027410832 0.008809117 0.008809117
chr14: 21167513-21168761 0.00025544 0.027452953 0.008809117
0.008809117 chrX: 23783663-23784592 0.000269284 0.028436048
0.006992237 0.006992237 chr12: 22218054-22218608 0.00028048
0.029277918 0.008258548 0.008258548 chr13: 114203739-114204542
0.0002876 0.029849598 0.008148434 0.008148434 chr7:
127233551-127233665 0.000296624 0.030160322 0.007212465 0.007212465
chr1: 168211738-168212378 0.000297236 0.030160322 0.007873149
0.007873149 chr7: 80551580-80551675 0.000309825 0.030524412
0.007818092 0.007818092 chr5: 149011544-149014531 0.000312739
0.030524412 0.008974288 0.008974288 chr6: 125583979-125585553
0.000314397 0.030524412 0.007377636 0.007377636 chr22:
39190072-39190148 0.00031763 0.030524412 0.007542807 0.007542807
chr14: 75201584-75203421 0.000321289 0.030617528 0.007597864
0.007597864 chr4: 142133947-142134031 0.00032197 0.030617528
0.010185542 0.010185542 chr6: 159420466-159421219 0.000327348
0.030966787 0.007652921 0.007652921 chr7: 142637438-142637955
0.000329233 0.030983765 0.008423719 0.008423719 chr1:
38019606-38019905 0.000356182 0.03317611 0.007763035 0.007763035
chr12: 112590538-112591407 0.000369367 0.0338033 0.009084402
0.009084402 chr8: 11643471-11644855 0.000381186 0.0338033
0.008699003 0.008699003 chrX: 99986990-99987110 0.000382884
0.0338033 0.008093377 0.008093377 chr1: 11865403-11866977
0.000384771 0.0338033 0.008203491 0.008203491 chr17:
19578870-19580909 0.000386887 0.0338033 0.008258548 0.008258548
chr1: 11322501-11322608 0.000388904 0.0338033 0.008313605
0.008313605 chr22: 29449566-29453475 0.000393128 0.033840648
0.008368662 0.008368662 chr6: 3157640-3157809 0.000399369
0.033903107 0.008423719 0.008423719 chr17: 12893348-12894960
0.000403186 0.033903107 0.00858889 0.00858889 chr1:
110888929-110889299 0.00040617 0.033963425 0.008643946 0.008643946
chr7: 227553-229557 0.000407643 0.033963425 0.008699003 0.008699003
chr21: 39288186-39288749 0.000413797 0.034004231 0.01040577
0.01040577 chr13: 21635484-21635718 0.000415622 0.034004231
0.008809117 0.008809117 chr3: 68981390-68981761 0.000421217
0.034068108 0.011561967 0.011561967
chr17: 56032585-56032684 0.000423903 0.034068108 0.00930463
0.00930463 chr11: 94861540-94865809 0.000425781 0.034068108
0.008919231 0.008919231 chr9: 5339535-5339873 0.000433669
0.034246655 0.010846226 0.010846226 chr8: 22291403-22291642
0.00045167 0.035043161 0.01222265 0.01222265 chrX: 2799092-2800859
0.000454498 0.035043161 0.008974288 0.008974288 chr5:
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chr3: 33138210-33138293 0.000460544 0.035043161 0.012057479
0.012057479 chr17: 74639589-74639894 0.000462776 0.035043161
0.009139459 0.009139459 chr4: 108871400-108874613 0.000462962
0.035043161 0.009194516 0.009194516 chr13: 24476755-24476794
0.000463125 0.035043161 0.009249573 0.009249573 chr2:
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chr7: 99573567-99573780 0.000464978 0.035043161 0.011617024
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0.00930463 0.00930463 chr15: 90286522-90286868 0.000481285
0.035534876 0.009359687 0.009359687 chr3: 132086547-132087142
0.000517458 0.037444565 0.009579915 0.009579915 chr1:
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chr16: 13328886-13329566 0.000529298 0.037486096 0.010901283
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0.009745086 0.009745086 chr7: 30168881-30170096 0.000535569
0.037486096 0.01095634 0.01095634 chr2: 231742722-231743963
0.000536517 0.037486096 0.011947366 0.011947366 chr15:
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chr8: 105478884-105479281 0.000559086 0.038464661 0.014535044
0.014535044 chr20: 49307662-49308065 0.000567068 0.038720521
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chr3: 195808701-195809060 0.000653258 0.041198377 0.01150691
0.01150691 chr10: 128994260-128994422 0.000671462 0.041773747
0.010240599 0.010240599 chr19: 18474200-18480763 0.000672614
0.041773747 0.013268733 0.013268733 chr12: 89913184-89918583
0.00067673 0.041773747 0.010846226 0.010846226 chr8:
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chr12: 112459953-112461255 0.000682814 0.041773747 0.010460827
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0.000707484 0.042460748 0.016572152 0.016572152 chr15:
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chr2: 219157188-219157309 0.000729631 0.04274929 0.016572152
0.016572152 chr2: 103459870-103460352 0.000751677 0.043341943
0.011011397 0.011011397 chr1: 24861582-24863506 0.000784044
0.043808512 0.011231625 0.011231625 chrX: 19140559-19140755
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chr2: 231911596-231914434 0.000799811 0.043922586 0.011451853
0.011451853 chr8: 142201372-142205907 0.000802553 0.043922586
0.015471012 0.015471012 chr12: 47226109-47226191 0.000802857
0.043922586 0.016462038 0.016462038 chr4: 8442374-8442450
0.000819972 0.044641533 0.018223862 0.018223862 chr17:
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chr22: 34318608-34318829 0.000854631 0.045631286 0.016737323
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0.011617024 0.011617024 chrX: 12738647-12742642 0.000858999
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0.000864966 0.045708659 0.018774432 0.018774432 chr21:
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chr4: 6619106-6625089 0.000877403 0.045925836 0.014094588
0.014094588 chr16: 4986984-4987136 0.000883987 0.046137514
0.011782195 0.011782195 chr5: 140389211-140391929 0.000891792
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0.000918534 0.047530856 0.017177779 0.017177779 chr1:
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chr3: 48340444-48340743 0.00093681 0.047661833 0.018003634
0.018003634 chr11: 62323634-62323719 0.000950347 0.047947664
0.018333976 0.018333976 chr12: 13366614-13369708 0.00096088
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0.000974474 0.048758299 0.0197104 0.0197104 chr17:
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chr10: 115489069-115490662 0.000993279 0.049024274 0.012167593
0.012167593 chr13: 36871773-36871977 0.00100519 0.049309634
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chr6: 149394968-149398126 0.001040999 0.05009999 0.01277322
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chr12: 108154733-108155049 0.001068068 0.050387852 0.012608049
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chr15: 90293739-90294541 0.001183079 0.053586679 0.013048505
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chr4: 111563074-111563279 0.001237943 0.054707452 0.021692452
0.021692452 chr7: 7575380-7575484 0.001246135 0.054730647
0.021417167 0.021417167 chr1: 19983358-19984945 0.001250341
0.054730647 0.022463249 0.022463249 chr17: 7990613-7991022
0.001260695 0.054730647 0.022463249 0.022463249 chr4:
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0.022738534 0.022738534 chr10: 117704168-117708503 0.001284378
0.054730647 0.013488961 0.013488961 chr15: 39887562-39891119
0.001284498 0.054730647 0.013544018 0.013544018 chr7:
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chr7: 6590638-6591067 0.001292708 0.054730647 0.013709189
0.013709189 chr13: 36047925-36050832 0.001312128 0.055295099
0.021417167 0.021417167 chr5: 171433461-171433877 0.001336152
0.055965232 0.01734295 0.01734295 chr16: 20911525-20911706
0.001337274 0.055965232 0.017673292 0.017673292 chr2:
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chr2: 175351600-175351822 0.001359864 0.056348645 0.018499147
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0.013929417 0.013929417 chr16: 16317255-16317351 0.00137118
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chr20: 8000084-8000476 0.001381424 0.056348645 0.022243022
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chr18: 71958981-71959251 0.001437928 0.057629628 0.021527281
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chr14: 21161705-21162338 0.001492678 0.058682923 0.015856411
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chr17: 42255572-42256451 0.001656546 0.062263442 0.021967737
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chr18: 19284464-19284766 0.001741729 0.064353713 0.022848648
0.022848648 chr3: 113005521-113006303 0.001746759 0.064353713
0.016957551 0.016957551 chr22: 30685281-30685616 0.001754562
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0.001766266 0.064581327 0.025986896 0.025986896 chr19:
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chrX: 120181461-120183794 0.001770715 0.064581327 0.025491384
0.025491384 chrX: 47064319-47065264 0.00178612 0.065012604
0.020866597 0.020866597 chr5: 125930698-125931110 0.001796019
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0.001809339 0.065464189 0.026977922 0.026977922 chr1:
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chr22: 40366908-40369725 0.001844113 0.066010185 0.025821725
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0.001876261 0.066300655 0.02609701 0.02609701 chr16:
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chr9: 119158787-119164601 0.001925722 0.067433539 0.028079062
0.028079062 chr2: 227659704-227664475 0.001946872 0.067611907
0.021527281 0.021527281 chr19: 46148530-46148726 0.001983165
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chr12: 102079359-102079796 0.002026334 0.068739822 0.029125145
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chr3: 159614511-159615149 0.002036119 0.068739822 0.022518306
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0.027143093 chr6: 144385587-144385735 0.002161872 0.070749694
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chr9: 4662297-4665256 0.002522928 0.077274787 0.03231845 0.03231845
chr14: 23904828-23904927 0.002549612 0.077741827 0.015801354
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chr14: 20881563-20881580 0.002655978 0.079071281 0.015526069
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0.029785828 0.029785828 chr22: 24890657-24891042 0.002694653
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0.021582338
chr9: 100845127-100845357 0.00273199 0.079648701 0.0295656
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0.033639817 0.033639817 chr10: 36810648-36813162 0.002749615
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chr7: 92465791-92465908 0.002770379 0.079997448 0.033804988
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chr1: 54483764-54483856 0.002907663 0.081412629 0.024665529
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chr12: 101521638-101522419 0.002977359 0.08168847 0.033915102
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0.032813962 chr14: 76446884-76448092 0.003050227 0.08306038
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chr18: 72775105-72777628 0.003165011 0.085014912 0.03705335
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chr3: 169487108-169487683 0.003280782 0.086696722 0.035952211
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0.033860045 0.033860045 chr7: 102301592-102301847 0.003300147
0.08687039 0.016021582 0.016021582 chr2: 169764077-169766505
0.003372886 0.08827339 0.017177779 0.017177779 chr10:
127697622-127698161 0.003486343 0.090400812 0.03121731 0.03121731
chr1: 68153343-68154021 0.003501622 0.090469355 0.037769091
0.037769091 chr14: 93651154-93651260 0.003532022 0.090948774
0.016131696 0.016131696 chr9: 102625901-102629173 0.003536498
0.090948774 0.035016242 0.035016242 chr20: 42939615-42939809
0.003540207 0.090948774 0.0346859 0.0346859 chr2:
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chr4: 175443509-175444305 0.003551326 0.090977065 0.02609701
0.02609701 chr1: 24740163-24743424 0.003572886 0.091143709
0.03650278 0.03650278 chr1: 113499460-113499635 0.003587275
0.091208876 0.038870231 0.038870231 chr10: 14816251-14816896
0.00359771 0.091264254 0.022793591 0.022793591 chr12:
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chr16: 88634958-88636548 0.00362599 0.091470629 0.019269944
0.019269944 chr4: 100212053-100212185 0.003639167 0.09167571
0.034465672 0.034465672 chr8: 1728415-1734738 0.003672878
0.092268989 0.039530914 0.039530914 chr11: 67124213-67124443
0.003683245 0.092274168 0.02884986 0.02884986 chr14:
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chr19: 45826078-45826233 0.003705532 0.092577124 0.027638606
0.027638606 chr6: 20212366-20212670 0.003743468 0.092868242
0.037108407 0.037108407 chr9: 130869307-130871524 0.003772717
0.093229751 0.01624181 0.01624181 chr9: 86258343-86259045
0.003800119 0.09365204 0.028794803 0.028794803 chr11: 626020-626078
0.003822747 0.093940709 0.039475858 0.039475858 chr16:
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chr12: 52470569-52471278 0.003836004 0.094026103 0.017453064
0.017453064 chr3: 143767509-143767561 0.003897344 0.095018782
0.038319661 0.038319661 chr16: 76592386-76593135 0.003922446
0.095100371 0.018003634 0.018003634 chr6: 139113885-139114456
0.003932856 0.095100371 0.038594946 0.038594946 chr17:
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chr10: 135336774-135337062 0.00393904 0.095100371 0.038980345
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0.039200573 0.039200573 chr4: 7940727-7942023 0.003953134
0.095100371 0.040026427 0.040026427 chr19: 35614344-35615227
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chr11: 125301061-125303285 0.004029966 0.095884062 0.032758905
0.032758905 chr8: 27401960-27403081 0.004038502 0.095884062
0.03578704 0.03578704 chr16: 81411019-81413940 0.004051327
0.095937748 0.029510543 0.029510543 chr2: 179695391-179695529
0.004079477 0.096315629 0.033474646 0.033474646 chr3:
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chr11: 125366403-125369424 0.004125875 0.096522303 0.040907339
0.040907339 chr8: 27337285-27337400 0.004139783 0.096522303
0.042393878 0.042393878 chr6: 170713850-170716153 0.004156806
0.096794954 0.039475858 0.039475858 chr19: 52034835-52035110
0.004188755 0.097074302 0.028519518 0.028519518 chr2:
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chr8: 121825324-121825513 0.004266128 0.098207447 0.043329846
0.043329846 chr10: 61122866-61122939 0.004276251 0.098315877
0.043219732 0.043219732 chr7: 98030113-98030380 0.004283229
0.098351823 0.03066674 0.03066674 chr5: 131630870-131631008
0.004315256 0.098553166 0.035566812 0.035566812 chrX:
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chr3: 113346492-113348425 0.004398853 0.098637481 0.0445411
0.0445411 chr1: 111893880-111895635 0.004436675 0.099254224
0.043384903 0.043384903 chr13: 111521577-111522162 0.004448077
0.099254224 0.029400429 0.029400429 chr1: 201860927-201861434
0.004454992 0.099254224 0.025766669 0.025766669 chr11:
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chr7: 49951629-49952138 0.004464114 0.099254224 0.038870231
0.038870231 chr12: 46663762-46663800 0.004464609 0.099254224
0.044100644 0.044100644 chr17: 71258247-71258491 0.004476868
0.099271066 0.041182624 0.041182624 chr1: 156108870-156109880
0.004478365 0.099271066 0.016517095 0.016517095 chr19:
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chr7: 134264258-134264592 0.004537761 0.099781299 0.039696085
0.039696085 chr7: 4897363-4901625 0.004590477 0.1005752 0.044596157
0.044596157 chr2: 11317862-11319000 0.004601586 0.100593449
0.045587183 0.045587183 chr14: 39900767-39901704 0.004620935
0.100593449 0.036667951 0.036667951 chr9: 131703723-131704320
0.004653093 0.100852182 0.016572152 0.016572152 chr1:
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chr3: 41301355-41301587 0.004722562 0.101389943 0.041457909
0.041457909 chr4: 31144094-31144728 0.004771765 0.102204685
0.039530914 0.039530914 chr1: 203765436-203769686 0.004792822
0.102293798 0.035071299 0.035071299 chr19: 3543826-3544028
0.00483625 0.102737778 0.037548863 0.037548863 chr22:
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chr15: 99791359-99791422 0.004859132 0.102862951 0.046027639
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0.016682266 0.016682266 chr5: 32786339-32787256 0.004899715
0.10324075 0.040576997 0.040576997 chr2: 160918805-160919121
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chr3: 14814297-14814541 0.004973307 0.103891426 0.038539889
0.038539889 chr20: 55100838-55100981 0.004976264 0.103891426
0.045036613 0.045036613 chr10: 43762292-43762367 0.005031975
0.10463209 0.021857623 0.021857623 chr5: 80561957-80562216
0.005040636 0.10463209 0.04107251 0.04107251 chr6:
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chr9: 5304369-5304969 0.005080302 0.104919288 0.041127567
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0.016847437 0.016847437 chr12: 50236168-50236912 0.005124504
0.105409257 0.045036613 0.045036613 chr14: 95942014-95942173
0.0051347 0.105428918 0.045752354 0.045752354 chr13:
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chr3: 38178355-38178733 0.005154483 0.105428918 0.041127567
0.041127567 chr10: 62761156-62761198 0.005169761 0.105609324
0.046468094 0.046468094 chr14: 24114350-24114848 0.005183255
0.105609324 0.047018664 0.047018664 chr19: 53077329-53077383
0.005187576 0.105609324 0.037989319 0.037989319 chrX:
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chr22: 17612504-17612994 0.00520967 0.105609324 0.025931839
0.025931839 chr15: 100273489-100273766 0.005217245 0.105609324
0.040191598 0.040191598 chr19: 57802066-57805436 0.005240306
0.105872839 0.04343996 0.04343996 chr1: 110052041-110052360
0.005247045 0.105891205 0.044871442 0.044871442 chr19:
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chr1: 235667440-235667781 0.005309579 0.106561188 0.044706271
0.044706271 chr5: 180631588-180632293 0.005350621 0.107030103
0.040356769 0.040356769 chr7: 134849169-134850650 0.005371153
0.107215322 0.044210758 0.044210758 chr1: 203054618-203055164
0.005389395 0.107215322 0.016902494 0.016902494 chr22:
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chr14: 59950207-59951148 0.005452342 0.107926139 0.049441172
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0.038925288 0.038925288 chr3: 159614511-159615155 0.00553005
0.108469 0.018223862 0.018223862 chr22: 43411026-43411151
0.005558398 0.108672962 0.041953422 0.041953422 chr3:
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chr6: 147705849-147708707 0.005594365 0.109141203 0.043109618
0.043109618 chr10: 43991463-43991517 0.005620169 0.109442547
0.041017453 0.041017453 chr6: 123384818-123385612 0.005746878
0.110636432 0.039806199 0.039806199 chr2: 168114366-168116263
0.005747901 0.110636432 0.025050928 0.025050928 chr11:
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chr1: 39876150-39882154 0.005784188 0.1108209 0.049441172
0.049441172 chr21: 47648347-47648738 0.005807752 0.111151912
0.045311898 0.045311898 chr8: 75233143-75233563 0.005847533
0.111316988 0.042944448 0.042944448 chr17: 46135656-46138906
0.005851836 0.111316988 0.026757694 0.026757694 chr3:
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chr17: 11461070-11462196 0.005873524 0.111316988 0.03650278
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0.048174861 0.048174861 chr11: 4730834-4731698 0.005890874
0.111454101 0.036998293 0.036998293 chr10: 75457290-75457639
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chr1: 200143090-200146552 0.005966581 0.112219245 0.018058691
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0.112453997 0.044596157 0.044596157 chr2: 182794287-182795465
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chr8: 12613432-12613582 0.00605405 0.112819565 0.02538127
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0.045366955 0.045366955 chr8: 74235147-74237516 0.006096308
0.112957258 0.017122722 0.017122722 chr9: 36276890-36277053
0.006098553 0.112957258 0.048615317 0.048615317 chr11:
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chr14: 23834216-23834961 0.006160456 0.113136859 0.044265815
0.044265815 chr17: 46198596-46200105 0.006240059 0.113793372
0.04052194 0.04052194 chr22: 50450973-50451088 0.006301388
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0.006314237 0.114456571 0.037383692 0.037383692 chr5:
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chr11: 31451817-31453396 0.006451988 0.11536742 0.049881627
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chr21: 33765077-33765335 0.006703042 0.117712421 0.0496614
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0.006714203 0.117712421 0.045752354 0.045752354 chr7:
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chr4: 6302383-6304992 0.006822582 0.118809741 0.048505203
0.048505203 chr14: 65007185-65009955 0.00687538 0.119044347
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0.006926867 0.119383107 0.017287893 0.017287893 chr2:
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chr3: 9934492-9936033 0.006958825 0.11946421 0.046853493
0.046853493 chr7: 1097127-1098897 0.007038213 0.119833972
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chr10: 120355027-120355160 0.007235098 0.120450124 0.022738534
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chr5: 140389211-140391929 0.007450363 0.122900837 0.047183835
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chr12: 124242473-124245549 0.007585745 0.123791448 0.046798436
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chr12: 53646601-53648189 0.007687785 0.123982656 0.017398007
0.017398007 chr22: 50050271-50051190 0.007712554 0.124077157
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chr11: 125136535-125136741 0.007905147 0.12572784 0.039365744
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chr20: 61167650-61167971 0.009052096 0.134113878 0.049496229
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chr20: 6034475-6034695 0.009551555 0.138124918 0.024500358
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chr10: 76868766-76868976 0.010291015 0.143011251 0.043715245
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chr17: 10325246-10325267 0.011183659 0.148377506 0.026041953
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chr2: 28634745-28640179 0.012312384 0.155291764 0.045532126
0.045532126 chr22: 20137990-20138399 0.013677005 0.162105645
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chr5: 180000987-180005405 0.019446262 0.188776567 0.044155701
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chr1: 226496809-226497570 0.014828474 0.167285451 0.045366955
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chr5: 56558420-56560505 0.012981899 0.158781296 0.017563178
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chr1: 185069331-185071740 0.011903263 0.153135566 0.029510543
0.029510543 chr17: 58023911-58027925 0.011632685 0.151675849
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chr9: 130457272-130457460 0.010347357 0.143355492 0.032703848
0.032703848 chr6: 84418064-84419410 0.010266638 0.142891143
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0.009830751 0.139750517 0.026207124 0.026207124 chr1:
92764481-92764544 0.009611488 0.138500189 0.04911083 0.04911083
chr5: 68709857-68710628 0.009465185 0.137886794 0.026812751
0.026812751 chr12: 51566083-51566926 0.009363899 0.136937591
0.02664758 0.02664758 chr12: 133532828-133532892 0.009352732
0.136937591 0.048340032 0.048340032 chr3: 69129484-69129559
0.008962241 0.133646293 0.043384903 0.043384903 chr2:
44222912-44223144 0.008953547 0.133626356 0.048395089 0.048395089
chr12: 106697789-106698057 0.008624532 0.130213948 0.046468094
0.046468094 chr19: 11978120-11980306 0.008487262 0.129047959
0.01915983 0.01915983 chr17: 30714772-30714780 0.008349022
0.128620259 0.04399053 0.04399053 chr3: 178984436-178984790
0.008225877 0.127371355 0.018774432 0.018774432 chr3:
3192223-3192563 0.008095056 0.126641267 0.048395089 0.048395089
chr2: 37193372-37193615 0.008031757 0.126088956 0.042614106
0.042614106 chr19: 34718269-34720420 0.008031588 0.126088956
0.046137753 0.046137753 chr5: 86708251-86708836 0.007979619
0.126029403 0.0295656 0.0295656 chr19: 12662143-12662327
0.007968372 0.1259613 0.026041953 0.026041953 chr19:
23941548-23941693 0.007903195 0.12572784 0.038815174 0.038815174
chr2: 203103162-203103331 0.007770669 0.124580756 0.035346584
0.035346584 chr11: 85563599-85565986 0.007768077 0.124580756
0.047679348 0.047679348 chr14: 39649706-39652422 0.007699853
0.123982656 0.049496229 0.049496229 chr8: 142012112-142012315
0.007617257 0.123967682 0.035291527 0.035291527 chr20:
57617753-57617964 0.007470271 0.122900837 0.044981556 0.044981556
chr13: 47371239-47371367 0.00746628 0.122900837 0.037548863
0.037548863 chr21: 40721385-40721573 0.007431424 0.122900837
0.01734295 0.01734295 chr7: 79846618-79848718 0.007217627
0.120269498 0.041843308 0.041843308 chr19: 57764440-57774106
0.007213586 0.120269498 0.045036613 0.045036613 chr16:
3367189-3368574 0.007195218 0.120269498 0.027583549 0.027583549
chr15: 60771201-60771344 0.007083234 0.120011929 0.040742168
0.040742168 chr17: 8286474-8286568 0.007079283 0.120011929
0.038319661 0.038319661 chr6: 168720067-168720434 0.007061216
0.119974623 0.029895942 0.029895942 chr14: 35008760-35008943
0.007036828 0.119833972 0.041953422 0.041953422 chr2:
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chr13: 41701704-41706882 0.006991002 0.119790156 0.040576997
0.040576997 chr5: 140602930-140605858 0.006908505 0.119276786
0.047128778 0.047128778 chr12: 75905292-75905416 0.006889135
0.119114534 0.017232836 0.017232836 chr7: 29552179-29553944
0.006871423 0.119044347 0.032593735 0.032593735 chr19:
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chr11: 75851754-75854239 0.006849485 0.119044347 0.045146727
0.045146727 chr3: 93747210-93747454 0.006780221 0.118195788
0.048450146 0.048450146 chr17: 65739858-65740318 0.006746884
0.118057478 0.037163464 0.037163464 chr16: 28331396-28335170
0.006597992 0.116688728 0.044871442 0.044871442 chr11:
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chrY: 21765682-21768160 0.006547321 0.116473052 0.017177779
0.017177779 chr15: 59949322-59949740 0.006441004 0.11536742
0.047789462 0.047789462 chr8: 141524392-141527236 0.006405193
0.115185655 0.047293949 0.047293949 chr1: 46153654-46153785
0.006381042 0.114979041 0.047349006 0.047349006 chr18:
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chr19: 35174896-35177302 0.006271246 0.114247377 0.035566812
0.035566812 chr4: 170192009-170192256 0.006138078 0.11306887
0.0496614 0.0496614 chr10: 74927623-74927853 0.00612095 0.112957258
0.042559049 0.042559049 chr5: 170738392-170739138 0.006120628
0.112957258 0.048615317 0.048615317 chr2: 217069910-217071026
0.006062514 0.112819565 0.042338821 0.042338821 chr16:
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chr8: 82644987-82645138 0.006017179 0.112670125 0.04217365
0.04217365 chr2: 238166072-238166319 0.00595458 0.112191938
0.046743379 0.046743379 chr22: 41252434-41253026 0.0059326
0.111893883 0.046413037 0.046413037 chr19: 21950228-21950330
0.005819824 0.111151912 0.017122722 0.017122722 chr1:
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chr12: 72070468-72074419 0.005759067 0.110636432 0.019545229
0.019545229 chr13: 37633616-37633850 0.005722694 0.11057584
0.017012608 0.017012608 chr2: 136481506-136482840 0.005713669
0.110519039 0.03997137 0.03997137 chr9: 66553673-66555928
0.005693028 0.110354813 0.038594946 0.038594946 chr13:
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chr17: 4994791-4999668 0.005621863 0.109442547 0.046027639
0.046027639 chr1: 151141461-151142773 0.005557871 0.108672962
0.037989319 0.037989319 chr11: 32623824-32627808 0.00551587
0.108307841 0.045697297 0.045697297 chr8: 42029046-42029191
0.005503321 0.108178378 0.041733194 0.041733194 chr11:
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chr3: 32814948-32815367 0.005472663 0.107926139 0.016957551
0.016957551 chrX: 15682840-15683154 0.005472551 0.107926139
0.043605131 0.043605131 chr19: 36909393-36909558 0.00546732
0.107926139 0.017783406 0.017783406 chr14: 23240642-23241007
0.005461346 0.107926139 0.048229918 0.048229918 chr7:
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chr14: 30661071-30661104 0.005422494 0.107637992 0.045807411
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0.047734405 0.047734405 chr6: 10419650-10419892 0.005385422
0.107215322 0.046082696 0.046082696 chr15: 23334999-23335196
0.005371808 0.107215322 0.030336398 0.030336398 chr17:
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chr11: 73964536-73965748 0.005334853 0.106950258 0.048945659
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0.037218521 0.037218521 chr3: 64009480-64009658 0.005282864
0.106259871 0.040026427 0.040026427 chr15: 40331293-40331389
0.00527923 0.106259871 0.048119804 0.048119804 chr15:
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chr10: 60588520-60591195 0.005221287 0.105609324 0.042614106
0.042614106 chr16: 47177489-47177908 0.005219547 0.105609324
0.032869019 0.032869019 chr10: 124713530-124713919 0.005175308
0.105609324 0.032813962 0.032813962 chr9: 127951840-127952218
0.005152593 0.105428918 0.037273578 0.037273578 chr1:
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chr4: 120325655-120326749 0.005094908 0.104919288 0.038209547
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0.044981556 0.044981556 chrX: 24094838-24096088 0.005091703
0.104919288 0.033254418 0.033254418 chr2: 207582984-207583120
0.005047289 0.104650575 0.048119804 0.048119804 chr4:
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chr2: 109492543-109493034 0.005031342 0.10463209 0.038264604
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0.004937413 0.103435103 0.01679238 0.01679238 chr12:
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chr9: 97090889-97090926 0.004928103 0.103435103 0.04509167
0.04509167 chr8: 103136797-103137135 0.004896931 0.10324075
0.016737323 0.016737323 chr2: 99797169-99797521 0.004874899
0.102956744 0.021857623 0.021857623 chr5: 140579182-140582618
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chr12: 93894951-93897545 0.004827859 0.102718394 0.028409404
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0.043054561 0.043054561 chr5: 134735438-134735604 0.004788569
0.102293798 0.043164675 0.043164675 chr1: 235611984-235612283
0.004785093 0.102293798 0.034796014 0.034796014 chr19:
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chr18: 12884071-12884337 0.004719445 0.101389943 0.028464461
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0.036117381 0.036117381 chr16: 4322658-4323001 0.004705385
0.101380678 0.040301712 0.040301712 chr6: 32938355-32938493
0.004682181 0.101120629 0.046082696 0.046082696 chr6:
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chr12: 6756489-6756626 0.004664875 0.100902973 0.0445411 0.0445411
chr11: 3400267-3400448 0.004646004 0.100818853 0.031437538
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chr15: 83209176-83209208 0.004609523 0.100593449 0.034851071
0.034851071 chr10: 5498550-5500426 0.004561884 0.100069441
0.038925288 0.038925288 chr17: 50237283-50237377 0.004550985
0.099951077 0.043825359 0.043825359 chr4: 159825617-159829201
0.004503626 0.099271066 0.044486043 0.044486043 chr5:
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chr14: 36982316-36982990 0.004496721 0.099271066 0.043935473
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0.041788251 0.041788251 chr9: 104499562-104500862 0.004488935
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0.004454398 0.099254224 0.020536255 0.020536255 chr3:
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chr5: 98134164-98134347 0.004395858 0.098637481 0.016462038
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0.03925563 0.03925563 chr5: 154393314-154397692 0.004375655
0.098553166 0.03997137 0.03997137 chr1: 145440852-145442635
0.004372371 0.098553166 0.043274789 0.043274789 chr2:
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chr5: 1886975-1887350 0.004367596 0.098553166 0.031272367
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0.043495017 0.043495017 chr3: 138663065-138665982 0.004361352
0.098553166 0.038209547 0.038209547
chr9: 88897292-88897676 0.004347928 0.098553166 0.040632054
0.040632054 chr10: 98273267-98273675 0.00434507 0.098553166
0.034520729 0.034520729 chr2: 30862982-30867091 0.004338867
0.098553166 0.040136541 0.040136541 chr3: 197682620-197683481
0.004331408 0.098553166 0.026757694 0.026757694 chr5:
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chr6: 3982908-3984372 0.004303895 0.098553166 0.029840885
0.029840885 chr5: 171221568-171221602 0.004300314 0.098553166
0.037438749 0.037438749 chr4: 76911848-76912115 0.004254139
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0.004217669 0.097438673 0.034025216 0.034025216 chr17:
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chr16: 81110740-81110818 0.004190181 0.097074302 0.036667951
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0.00413916 0.096522303 0.037714034 0.037714034 chr9:
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chr7: 130144779-130146133 0.004116829 0.096482536 0.028684689
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0.004110184 0.096482536 0.025656555 0.025656555 chr3:
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chr1: 173793699-173793858 0.004081228 0.096315629 0.035842097
0.035842097 chr9: 37356831-37358146 0.004050647 0.095937748
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chr1: 25824754-25826700 0.003992587 0.095669326 0.034740957
0.034740957 chr13: 26594025-26599989 0.003972826 0.095321592
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0.003951763 0.095100371 0.041402852 0.041402852 chr16:
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chr6: 74233169-74233520 0.003934968 0.095100371 0.033199361
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chr14: 64108016-64108125 0.003816037 0.093916923 0.029015031
0.029015031 chr14: 20825209-20826063 0.003783766 0.09337573
0.039861256 0.039861256 chr8: 42229080-42229326 0.003752975
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0.003751362 0.092868242 0.035566812 0.035566812 chr11:
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chr11: 132204939-132206716 0.003738017 0.092868242 0.036227495
0.036227495 chr19: 58513763-58514717 0.003737347 0.092868242
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0.092868242 0.036723008 0.036723008 chr1: 40758116-40759856
0.003681105 0.092274168 0.029510543 0.029510543 chr12:
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chr11: 4673715-4676718 0.003621687 0.091470629 0.032098222
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0.027308264 0.027308264 chr12: 104359293-104359486 0.003590505
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0.003582254 0.091208876 0.016186753 0.016186753 chr19:
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chr12: 102224336-102224716 0.003564368 0.091143709 0.028684689
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0.00349355 0.090400812 0.016076639 0.016076639 chr19:
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chr8: 17104183-17104387 0.003462106 0.090089159 0.032153279
0.032153279 chr4: 88312012-88312538 0.003453466 0.089993264
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0.003382668 0.088402009 0.019930628 0.019930628 chr1:
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chr17: 36294031-36294915 0.003331502 0.087442296 0.028354347
0.028354347 chr22: 31363051-31364284 0.003316793 0.087182226
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chr12: 69783926-69784576 0.003216422 0.08553422 0.036612894
0.036612894 chr13: 100622380-100624163 0.003203139 0.085528988
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chr2: 47614696-47614740 0.003153567 0.084982538 0.034080273
0.034080273 chr9: 139304779-139305061 0.00315322 0.084982538
0.029730771 0.029730771 chr16: 332614-333003 0.003152829
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chr10: 33625122-33625190 0.003042761 0.08306038 0.016131696
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chr1: 2564304-2564481 0.002944605 0.081412629 0.015856411
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chr6: 76425100-76427997 0.002913874 0.081412629 0.023674503
0.023674503 chr8: 86129188-86129387 0.002913777 0.081412629
0.028519518 0.028519518 chr16: 19716437-19716880 0.002908979
0.081412629 0.015746297 0.015746297 chr1: 148025760-148025863
0.002904589 0.081412629 0.031877994 0.031877994 chr7:
155255065-155257526 0.002900458 0.081412629 0.0346859 0.0346859
chr14: 70826235-70826444 0.002879251 0.08133101 0.027638606
0.027638606 chr5: 140588268-140591696 0.002869414 0.081179389
0.024170016 0.024170016 chr6: 97345541-97345757 0.002861174
0.081129471 0.017453064 0.017453064 chr19: 21560190-21562104
0.002849301 0.081115772 0.033089247 0.033089247 chr5:
140557370-140560081 0.002846381 0.081115772 0.034465672 0.034465672
chr4: 55161291-55161439 0.002837998 0.081115772 0.032373507
0.032373507 chr17: 79771349-79771889 0.002816245 0.080681283
0.032924076 0.032924076 chr19: 52793318-52795977 0.002813154
0.080681283 0.0248307 0.0248307 chr1: 63788729-63790797 0.002798558
0.080555005 0.032813962 0.032813962 chr1: 147954634-147955419
0.002795098 0.080555005 0.027418378 0.027418378 chr12:
122496997-122499948 0.002757038 0.079738981 0.024885757 0.024885757
chr9: 123605014-123605229 0.00272948 0.079648701 0.015581126
0.015581126 chr2: 233412778-233415226 0.002724131 0.079648701
0.031052139 0.031052139 chr22: 49246569-49246724 0.002711088
0.079550065 0.029950999 0.029950999 chr17: 41154888-41154956
0.002707158 0.079550065 0.028079062 0.028079062 chr12:
123741359-123742506 0.002698823 0.079550065 0.033860045 0.033860045
chr6: 31937586-31940069 0.002692989 0.079550065 0.032538678
0.032538678 chr17: 5322673-5323000 0.002664297 0.079071281
0.023839674 0.023839674 chr8: 26227649-26230196 0.002663318
0.079071281 0.02719815 0.02719815 chr2: 74734702-74735707
0.002651333 0.079071281 0.032648791 0.032648791 chr10:
70968355-70968855 0.002650167 0.079071281 0.015471012 0.015471012
chrX: 70519791-70521018 0.002642471 0.079069514 0.030391455
0.030391455 chr2: 44547337-44548633 0.002636828 0.079069514
0.033254418 0.033254418 chr7: 87536502-87538856 0.002636013
0.079069514 0.032263393 0.032263393 chr19: 37019120-37019562
0.002631242 0.079069514 0.027032979 0.027032979 chr1:
149899617-149900236 0.002622595 0.079069514 0.027418378 0.027418378
chr4: 83822235-83822319 0.002584918 0.078401198 0.029400429
0.029400429 chr8: 19615360-19615540 0.002555298 0.077741827
0.015415956 0.015415956 chr6: 44221225-44221620 0.00255246
0.077741827 0.030997082 0.030997082 chr8: 54934622-54935089
0.002552422 0.077741827 0.029510543 0.029510543 chr4:
13485699-13485989 0.00249312 0.07662021 0.015966525 0.015966525
chr10: 61665879-61666414 0.002484359 0.076480369 0.030776854
0.030776854 chr15: 82939013-82939159 0.002477524 0.07639943
0.029235258 0.029235258 chr5: 170837530-170838141 0.002471593
0.07634617 0.02829929 0.02829929 chr5: 138665033-138667360
0.002449038 0.076037393 0.015305842 0.015305842 chr1:
150443036-150449042 0.00244694 0.076037393 0.017673292 0.017673292
chr19: 39303481-39303740 0.002406051 0.075346732 0.026812751
0.026812751 chr7: 143002032-143004789 0.002390425 0.074986674
0.030501569 0.030501569 chr14: 64804615-64805317 0.002359921
0.074281033 0.021472224 0.021472224 chr17: 44833167-44834830
0.002328796 0.073433881 0.029620657 0.029620657 chr11:
114284677-114284925 0.002325247 0.073433881 0.015195728 0.015195728
chr2: 180725827-180726232 0.002324535 0.073433881 0.015966525
0.015966525 chr19: 51587392-51587502 0.002287063 0.072893957
0.031272367 0.031272367 chr19: 52868950-52870375 0.002286182
0.072893957 0.020701426 0.020701426 chr14: 21737456-21737638
0.00227195 0.072893957 0.02428013 0.02428013 chr11:
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chr13: 79979835-79980612 0.002239673 0.072254321 0.030556626
0.030556626 chr5: 32601110-32604185 0.002216057 0.071875443
0.015085614 0.015085614 chr6: 53787432-53788919 0.002185744
0.071361233 0.020371084 0.020371084 chr11: 22644078-22647387
0.002137025 0.070316635 0.015030557 0.015030557 chr20:
52844491-52844591 0.002128905 0.070176597 0.0149755 0.0149755 chr6:
30613671-30614600 0.002127962 0.070176597 0.028134119 0.028134119
chr16: 70605575-70608820 0.002122664 0.070176597 0.030061113
0.030061113 chr16: 3355211-3355645 0.002117779 0.070176597
0.014920443 0.014920443 chr1: 161135146-161135513 0.002116353
0.070176597 0.024114959 0.024114959 chr8: 101733618-101735037
0.002096667 0.069874778 0.022463249 0.022463249 chr1:
151688094-151689290 0.002077995 0.069507577 0.025986896 0.025986896
chr9: 133376362-133376661 0.002058452 0.069108448 0.029510543
0.029510543 chr12: 3048476-3050306 0.002052882 0.069049055
0.029180202 0.029180202 chr4: 111120255-111120355 0.002043933
0.068875607 0.026317238 0.026317238 chr9: 19378705-19380252
0.002029563 0.068739822 0.023784617 0.023784617 chr10:
121302101-121302220 0.002017084 0.068739822 0.023454275 0.023454275
chr16: 277240-279462 0.002007769 0.068739822 0.027473435
0.027473435 chr19: 24309055-24312643 0.002000416 0.068739822
0.024335187 0.024335187 chrX: 152241317-152243401 0.001995419
0.068739822 0.022298079 0.022298079 chr1: 116609639-116612675
0.00198767 0.068739822 0.028134119 0.028134119 chr15:
69113036-69113236 0.001939615 0.067488924 0.024225073 0.024225073
chr11: 6463716-6463847 0.00193868 0.067488924 0.025931839
0.025931839 chr17: 4269565-4269969 0.001936683 0.067488924
0.014755272 0.014755272 chr17: 30228554-30228731 0.001926885
0.067433539 0.026812751 0.026812751 chr5: 178157556-178157703
0.001895907 0.06671121 0.021747509 0.021747509 chr14:
21464685-21465189 0.001894065 0.06671121 0.022298079 0.022298079
chr1: 144828540-144830302 0.001866021 0.066079013 0.016131696
0.016131696 chr16: 3284635-3285456 0.001860749 0.066079013
0.027253207 0.027253207 chr19: 33078158-33078322 0.001853504
0.066010185 0.026977922 0.026977922 chr1: 17766040-17766220
0.001853216 0.066010185 0.027693663 0.027693663 chr22:
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chr4: 96075698-96079599 0.001834474 0.065979296 0.014590101
0.014590101 chr2: 190339938-190340291 0.001834136 0.065979296
0.020040742 0.020040742 chr15: 52970768-52970820 0.001791727
0.065086286 0.020976711 0.020976711 chr3: 62359972-62359999
0.001765165 0.064581327 0.026922865 0.026922865 chr14:
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chr9: 131303380-131304567 0.001740684 0.064353713 0.01734295
0.01734295 chr19: 36726560-36729673 0.001722816 0.064121923
0.019820514 0.019820514 chr11: 76731317-76737841 0.001680831
0.062816721 0.023068876 0.023068876 chr5: 44816544-44820530
0.001641165 0.061976164 0.017012608 0.017012608 chr20:
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chr2: 175113179-175113426 0.001629985 0.061936008 0.014479987
0.014479987 chr11: 43876693-43878167 0.001615677 0.061650304
0.022132908 0.022132908 chr6: 111214678-111216916 0.001613961
0.061650304 0.014369873 0.014369873 chr2: 44999174-44999731
0.001613847 0.061650304 0.023564389 0.023564389 chr17:
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chr14: 91883974-91884152 0.001530468 0.059652123 0.015085614
0.015085614 chr1: 85514078-85514182 0.001525996 0.059605736
0.024720586 0.024720586 chr11: 26744853-26744974 0.001508748
0.059059014 0.025546441 0.025546441 chr3: 52089865-52090566
0.001508582 0.059059014 0.022298079 0.022298079 chr11:
102340904-102341115 0.001485218 0.058516288 0.021031768 0.021031768
chr6: 27368071-27371683 0.001476676 0.058433244 0.014149645
0.014149645 chr7: 19156293-19157295 0.001471295 0.058397855
0.015526069 0.015526069 chrX: 129063311-129063737 0.001461047
0.058195149 0.020371084 0.020371084 chr21: 18965469-18965897
0.001396915 0.056634289 0.014094588 0.014094588 chr5:
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chr7: 149470196-149470568 0.001383664 0.056348645 0.022683477
0.022683477 chr14: 89088611-89088615 0.001383605 0.056348645
0.014039531 0.014039531 chr6: 137112847-137113656 0.001365598
0.056348645 0.023454275 0.023454275 chr1: 155707947-155708803
0.001353654 0.056261816 0.01387436 0.01387436 chr12:
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chr12: 122985186-122985518 0.001329462 0.055895875 0.013764246
0.013764246 chr20: 13797763-13799067 0.001301059 0.054956129
0.021472224 0.021472224 chr20: 20693017-20693266 0.001289806
0.054730647 0.014204702 0.014204702 chr17: 27940371-27941779
0.001287374 0.054730647 0.013599075 0.013599075
chr2: 24991089-24993571 0.001282497 0.054730647 0.021857623
0.021857623 chr1: 2706067-2706280 0.001276855 0.054730647
0.015471012 0.015471012 chr11: 61136068-61136683 0.001269747
0.054730647 0.020591312 0.020591312 chr5: 72801016-72801460
0.001259835 0.054730647 0.022518306 0.022518306 chr12:
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chr11: 77348634-77348850 0.001244205 0.054730647 0.013378847
0.013378847 chr11: 64940653-64940715 0.00123731 0.054707452
0.018223862 0.018223862 chr1: 169555466-169555826 0.00121279
0.054389907 0.013268733 0.013268733 chr1: 113212613-113214241
0.00120243 0.054058764 0.013213676 0.013213676 chr11:
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chr6: 119228566-119230332 0.001187702 0.053662274 0.013103562
0.013103562 chr9: 96082648-96082854 0.001181597 0.053586679
0.018884546 0.018884546 chr16: 48419114-48419361 0.001173876
0.053570624 0.012993448 0.012993448 chr6: 117252493-117253326
0.001165397 0.0534523 0.020921654 0.020921654 chr5:
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chr1: 203821268-203823252 0.001108231 0.051612302 0.01277322
0.01277322 chr12: 57125273-57125412 0.001072585 0.05046987
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0.050387852 0.012552992 0.012552992 chr22: 41255552-41258130
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chr12: 21391912-21392180 0.00104238 0.05009999 0.012387821
0.012387821 chr4: 165878099-165880274 0.001026914 0.049738242
0.012332764 0.012332764 chr13: 53216540-53217919 0.001026838
0.049738242 0.019985685 0.019985685 chr7: 16921567-16921611
0.001026105 0.049738242 0.020095799 0.020095799 chr10:
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chr12: 15114470-15114662 0.000989776 0.049024274 0.012057479
0.012057479 chr9: 74525549-74525847 0.000977152 0.048758299
0.012002423 0.012002423 chr4: 77996624-77997158 0.000969463
0.048641844 0.011947366 0.011947366 chr22: 29137756-29138410
0.000946731 0.047898273 0.012442878 0.012442878 chr4:
69696317-69696914 0.0009412 0.047751429 0.01915983 0.01915983 chr4:
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chr4: 169931098-169931426 0.000927605 0.047587285 0.017453064
0.017453064 chr1: 46158875-46160115 0.000926916 0.047587285
0.012387821 0.012387821 chr19: 11494768-11495018 0.000922982
0.047587285 0.013654132 0.013654132 chr6: 32151657-32152101
0.000903309 0.046876568 0.018003634 0.018003634 chrX:
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chr11: 1481729-1483919 0.000867469 0.045708659 0.01442493
0.01442493 chr10: 35927176-35930362 0.000859214 0.045631286
0.017398007 0.017398007 chr5: 34924951-34926101 0.000856629
0.045631286 0.011892309 0.011892309 chr11: 108810972-108811657
0.000832793 0.045017925 0.011561967 0.011561967 chr6:
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chr5: 179498455-179499118 0.000820915 0.044641533 0.016902494
0.016902494 chr2: 207653542-207657233 0.000797601 0.043922586
0.017508121 0.017508121 chr1: 32801547-32801980 0.000791124
0.043808512 0.011396796 0.011396796 chr15: 58073773-58074960
0.000790373 0.043808512 0.011341739 0.011341739 chr5:
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chr11: 58345458-58345693 0.000786872 0.043808512 0.017453064
0.017453064 chr1: 167757056-167761156 0.000777688 0.043808512
0.011176568 0.011176568 chr1: 154531383-154531504 0.000777153
0.043808512 0.011121511 0.011121511 chr21: 27107163-27107984
0.000776889 0.043808512 0.012828277 0.012828277 chr1:
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chr14: 20925149-20925933 0.000771737 0.043808512 0.012718163
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0.015856411 0.015856411 chr9: 33798853-33799230 0.000744555
0.043068013 0.01095634 0.01095634 chr9: 74597572-74600970
0.000742855 0.043068013 0.010901283 0.010901283 chr11:
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chr6: 47009926-47010099 0.000734128 0.042755513 0.016351924
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0.016351924 0.016351924 chr6: 107979410-107981357 0.000718577
0.042513049 0.010791169 0.010791169 chr1: 151220338-151222012
0.000717051 0.042513049 0.013709189 0.013709189 chr12:
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chr1: 154243356-154243986 0.000713525 0.042513049 0.01387436
0.01387436 chr2: 9613044-9613230 0.000708342 0.042460748
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0.041773747 0.010625998 0.010625998 chr5: 68849396-68853931
0.000689997 0.041773747 0.010570941 0.010570941 chr1:
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chr12: 50492729-50494495 0.000677636 0.041773747 0.010350713
0.010350713 chr10: 33171620-33171802 0.000677312 0.041773747
0.010295656 0.010295656 chr7: 23571407-23571660 0.000656983
0.041289887 0.013929417 0.013929417 chr1: 2520848-2522908
0.000641426 0.040735055 0.011011397 0.011011397 chr21:
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chr6: 30530165-30531500 0.000634398 0.040555725 0.015360899
0.015360899 chr2: 223520734-223521056 0.000632879 0.040555725
0.012002423 0.012002423 chr12: 96437066-96437298 0.000632631
0.040555725 0.010185542 0.010185542 chr5: 140041763-140042064
0.000626233 0.040555725 0.013158619 0.013158619 chr1:
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chr10: 71871273-71872032 0.000616327 0.040555725 0.010020371
0.010020371 chr13: 103491900-103493885 0.000597551 0.039755743
0.010350713 0.010350713 chr1: 228353174-228353213 0.00059719
0.039755743 0.010846226 0.010846226 chr2: 42719976-42721237
0.000592999 0.039744051 0.011176568 0.011176568 chr1:
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chr3: 195310748-195311076 0.000575152 0.039125424 0.009965314
0.009965314 chr9: 129458572-129463311 0.000561861 0.038509773
0.013268733 0.013268733 chr11: 93583577-93583697 0.00054174
0.037555812 0.014039531 0.014039531 chr12: 56693943-56694176
0.000538947 0.037505344 0.009910257 0.009910257 chr22:
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chr19: 14201749-14201848 0.000530518 0.037486096 0.009690029
0.009690029 chr17: 44632896-44633016 0.000525864 0.037486096
0.010625998 0.010625998 chr7: 33148832-33149013 0.000509039
0.036982719 0.009524858 0.009524858 chr19: 20046830-20046860
0.000499745 0.036453301 0.009469801 0.009469801 chr15:
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chr1: 26233278-26233482 0.000496568 0.036453301 0.009414744
0.009414744 chr1: 222886085-222886552 0.000478764 0.035493035
0.013213676 0.013213676 chr13: 100637576-100639018 0.00047822
0.035493035 0.010625998 0.010625998 chr2: 181940922-181941312
0.000472014 0.035377477 0.012332764 0.012332764 chr8:
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chr6: 80751835-80752244 0.000437005 0.034360736 0.009579915
0.009579915 chr11: 49229843-49230222 0.00043239 0.034246655
0.009690029 0.009690029 chr11: 18127453-18127638 0.00043097
0.034246655 0.011011397 0.011011397 chr2: 74718607-74722013
0.000425021 0.034068108 0.011947366 0.011947366 chr2:
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chr1: 156051335-156051789 0.000415016 0.034004231 0.00875406
0.00875406 chr20: 45985400-45985567 0.000413714 0.034004231
0.011892309 0.011892309 chr6: 20490398-20493945 0.000402697
0.033903107 0.008533833 0.008533833 chr9: 17502548-17503921
0.000399995 0.033903107 0.008478776 0.008478776 chr11:
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chr16: 1374730-1377019 0.000390959 0.033814213 0.008919231
0.008919231 chr4: 85418711-85419603 0.000388972 0.0338033
0.011396796 0.011396796 chr1: 2345035-2345236 0.000387542 0.0338033
0.011066454 0.011066454 chr13: 37583320-37583750 0.000383013
0.0338033 0.008148434 0.008148434 chr6: 114332294-114332472
0.00038083 0.0338033 0.00803832 0.00803832 chr11: 94730187-94732682
0.000380412 0.0338033 0.007983263 0.007983263 chr7:
96639107-96640351 0.000379524 0.0338033 0.007928206 0.007928206
chr1: 43316593-43318148 0.000374998 0.0338033 0.007873149
0.007873149 chr6: 30620387-30620987 0.000368399 0.0338033
0.007818092 0.007818092 chr1: 38455541-38456593 0.000337962
0.031641224 0.007707978 0.007707978 chr16: 3450944-3451030
0.000317223 0.030524412 0.00748775 0.00748775 chr2:
27886195-27886676 0.000315018 0.030524412 0.007432693 0.007432693
chr3: 131221573-131221827 0.000312506 0.030524412 0.010130485
0.010130485 chr6: 117890782-117891021 0.000309822 0.030524412
0.007322579 0.007322579 chr6: 37298819-37300746 0.00030641
0.030524412 0.007267522 0.007267522 chr19: 52531494-52531680
0.000301647 0.030437889 0.008148434 0.008148434 chr12:
76478346-76478813 0.000294718 0.030160322 0.007157408 0.007157408
chr6: 110797724-110797844 0.000290236 0.029952049 0.007102351
0.007102351 chr17: 38290531-38293040 0.000275367 0.028910303
0.007047294 0.007047294 chr2: 71192087-71192555 0.00026727
0.028388448 0.00693718 0.00693718 chr1: 236645566-236648026
0.000264197 0.028227163 0.006882123 0.006882123 chr1:
90398625-90402170 0.000252946 0.027410832 0.006827066 0.006827066
chr15: 34880591-34880704 0.000250304 0.027410832 0.007542807
0.007542807 chr17: 27277912-27278789 0.000250154 0.027410832
0.00748775 0.00748775 chr7: 50632981-50633154 0.000250135
0.027410832 0.006716952 0.006716952 chr10: 122348814-122349367
0.000249544 0.027410832 0.008533833 0.008533833 chr12:
54428061-54429145 0.000246644 0.027410832 0.007983263 0.007983263
chr3: 63849179-63849579 0.000246543 0.027410832 0.006606838
0.006606838 chr17: 57351011-57353322 0.000236747 0.027410832
0.006551781 0.006551781 chr19: 11529921-11530018 0.000212432
0.02572268 0.006331553 0.006331553 chr12: 54423414-54424607
0.00021234 0.02572268 0.007818092 0.007818092 chr6:
107372260-107372546 0.000211601 0.02572268 0.006661895 0.006661895
chr17: 27169675-27169841 0.000193726 0.024266551 0.006166382
0.006166382 chr12: 2113366-2113701 0.000172975 0.021961395
0.007818092 0.007818092 chr20: 62168437-62168723 0.000168353
0.021533748 0.007763035 0.007763035 chr20: 524315-524482
0.000167895 0.021533748 0.006111325 0.006111325 chr2:
40006253-40006407 0.000165764 0.021533748 0.006056268 0.006056268
chr1: 38061359-38061540 0.000165526 0.021533748 0.006001211
0.006001211 chr7: 40899914-40900362 0.000163423 0.021533748
0.006496724 0.006496724 chr12: 54448633-54449814 0.000153417
0.020640881 0.006772009 0.006772009 chr2: 86422460-86422893
0.000152321 0.020640881 0.006001211 0.006001211 chr4:
147442769-147443123 0.000145311 0.020358172 0.006111325 0.006111325
chr1: 145368440-145370303 0.000145073 0.020358172 0.005670869
0.005670869 chr6: 46669594-46672056 0.00014216 0.020358172
0.005505698 0.005505698 chr5: 136933886-136934068 0.000138325
0.020261212 0.005450641 0.005450641 chr4: 39529418-39529931
0.000133517 0.020041937 0.00528547 0.00528547 chr8:
145979576-145981802 0.000127134 0.019242801 0.005615812 0.005615812
chr11: 381668-382116 0.000126188 0.019242801 0.005230413
0.005230413 chr5: 68737358-68740157 0.000121712 0.019126366
0.005560755 0.005560755 chr1: 150325308-150325671 0.00011576
0.018606562 0.005065243 0.005065243 chr3: 53845139-53846490
0.000111313 0.018214263 0.004955129 0.004955129 chr9:
126030714-126030855 0.000110375 0.018214263 0.004845015 0.004845015
chrX: 109683117-109683461 0.000107624 0.018099813 0.005946154
0.005946154 chr5: 74072428-74072737 0.000105481 0.017905164
0.005065243 0.005065243 chr19: 19654489-19657468 9.78E-05
0.017086351 0.004679844 0.004679844 chr22: 19770836-19771116
9.30E-05 0.016887835 0.004845015 0.004845015 chr16:
11945264-11945442 8.79E-05 0.016293883 0.004459616 0.004459616
chr12: 56509926-56509935 8.68E-05 0.016256711 0.004900072
0.004900072 chr11: 18063910-18063973 8.50E-05 0.016078925
0.004900072 0.004900072 chr6: 111137010-111137161 5.67E-05
0.012121545 0.003964103 0.003964103 chr5: 11903928-11904155
5.64E-05 0.012121545 0.003909046 0.003909046 chr9:
23825803-23826335 5.63E-05 0.012121545 0.004404559 0.004404559
chr5: 137910926-137911133 5.62E-05 0.012121545 0.003853989
0.003853989 chr16: 15224943-15225458 5.55E-05 0.012121545
0.003798932 0.003798932 chr10: 115991244-115992063 5.54E-05
0.012121545 0.003743875 0.003743875 chr11: 49059029-49059579
5.36E-05 0.012121545 0.003798932 0.003798932 chrX:
135962755-135962939 4.64E-05 0.011520023 0.003413533 0.003413533
chr15: 74005274-74006859 4.35E-05 0.010985753 0.003633761
0.003633761 chr6: 76624529-76629254 3.98E-05 0.010632462
0.003193305 0.003193305 chr6: 105627707-105627870 3.80E-05
0.010304253 0.003138248 0.003138248 chr1: 224517772-224518089
3.80E-05 0.010304253 0.003138248 0.003138248 chr9:
93405033-93405386 3.72E-05 0.010304253 0.003083191 0.003083191
chr20: 1373477-1373806 3.37E-05 0.009557199 0.003028134 0.003028134
chr9: 131262345-131263239 3.28E-05 0.009557199 0.00291802
0.00291802 chr10: 124923335-124924886 3.21E-05 0.009557199
0.002973077 0.002973077 chr5: 133304136-133304478 3.20E-05
0.009557199 0.002807906 0.002807906 chr1: 84855461-84855640
2.97E-05 0.009293059 0.002752849 0.002752849 chr5:
79865972-79866307 2.72E-05 0.008978177 0.002697792 0.002697792
chr3: 132004083-132004254 2.23E-05 0.007783374 0.002532621
0.002532621 chr1: 40783259-40783488 2.03E-05 0.007236461
0.002477564 0.002477564 chr6: 111346605-111347303 2.02E-05
0.007236461 0.002422507 0.002422507 chr12: 82152992-82153332
2.02E-05 0.007236461 0.00236745 0.00236745 chr1: 76076724-76076801
2.00E-05 0.007236461 0.00236745 0.00236745 chr11: 94965320-94965705
1.94E-05 0.007236461 0.002257336 0.002257336 chr5:
102611597-102614361 1.15E-05 0.00499128 0.002147222 0.002147222
chr1: 166845396-166845564 7.77E-06 0.004015199 0.00181688
0.00181688 chr6: 28200339-28201260 7.13E-06 0.003810198 0.001761823
0.001761823 chr4: 122617735-122618268 5.57E-06 0.003261046
0.001596653 0.001596653 chr2: 203630168-203634480 5.50E-06
0.003261046 0.001486539 0.001486539 chr15: 82554954-82555104
5.43E-06 0.003261046 0.001431482 0.001431482 chr6:
46703286-46703430 5.40E-06 0.003261046 0.001376425 0.001376425
chr6: 24785865-24786327 5.24E-06 0.003261046 0.001321368
0.001321368 chr3: 175520792-175523428 4.73E-06 0.003261046
0.001211254 0.001211254 chr1: 70587462-70589164 4.71E-06
0.003261046 0.001156197 0.001156197 chr6: 38997880-38998301
4.60E-06 0.003261046 0.00110114 0.00110114 chr1: 31769457-31769662
4.57E-06 0.003261046 0.000991026 0.000991026 chr3: 3886047-3889387
3.97E-06 0.003261046 0.000880912 0.000880912 chr17: 4545517-4545589
3.58E-06 0.003261046 0.000825855 0.000825855 chr18:
55143668-55158530 3.36E-06 0.003261046 0.000770798 0.000770798
chr18: 63547636-63552376 2.83E-06 0.003261046 0.000715741
0.000715741 chr11: 129728468-129729898 2.23E-06 0.002893994
0.000660684 0.000660684 chr17: 38821255-38821393 2.07E-06
0.002893994 0.000605627 0.000605627 chr6: 107436293-107436473
2.06E-06 0.002893994 0.00055057 0.00055057 chr1:
180991774-180992047 2.03E-06 0.002893994 0.00055057 0.001806154
chr9: 114361882-114362135 2.00E-06 0.002893994 0.000495513
0.000495513 chr3: 193855471-193856521 2.00E-06 0.002893994
0.000440456 0.000440456 chr6: 38670746-38670917 1.86E-06
0.002893994 0.000385399 0.000385399 chr2: 71159896-71160576
1.78E-06 0.002893994 0.000330342 0.000330342 chr8:
136668468-136668965 1.67E-06 0.002893994 0.000275285
0.000275285
chr9: 79634570-79635869 5.60E-07 0.002542246 0.000220228
0.000220228 chr1: 31712340-31712401 0 0 0.000165171 0.000165171
chr6: 107780193-107780768 0 0 0.000165171 0.000165171 chr2:
181780999-181782519 0 0 0.000165171 0.000165171
[0414] All publications, patents, patent applications and accession
numbers mentioned in the above specification are herein
incorporated by reference in their entirety. Although the invention
has been described in connection with specific embodiments, it
should be understood that the invention as claimed should not be
unduly limited to such specific embodiments. Indeed, various
modifications and variations of the described compositions and
methods of the invention will be apparent to those of ordinary
skill in the art and are intended to be within the scope of the
following claims.
Sequence CWU 1
1
281621DNAHomo sapiens 1acacatggat attggatatc tgcataggca gcttgctcca
cgccagtgcc tacctgtgca 60gatgggaagg aaaggaaagt ggcaaggagg cagagaaagc
atctgtaccc ttacaatttg 120gtgagacaag aatgtatgaa ttcccacagg
tcaaattata atgaagaaag gaacctctct 180tgagtacaaa gagctaccta
tggtggtctg gagccggagg accacagcat caaaggatat 240aagatgcata
gccaactgag gaacctgagc aattaaagag atccacagtt aagtcacact
300taactggcac ttgtggaagc cccgcaaggc ctgaaggaga gctgacatag
gcaccccgga 360gagccagaat ctggatccca tcttaataag gccatgaaca
ccagtggaga agaggcagaa 420acaccaatgg ataaggaaca ttcacatctt
tcttcccatg tgcctctaag tgccagtgca 480ggccccacag gccaagctac
agggagaaag gagatgacgc aaaggaacct aactggactt 540taatcactag
aagtgagaag agaaatctat tggaacctcc caagataatg ccaagggtca
600aagggtgcgc agatacataa g 62121371DNAHomo sapiens 2accatggaaa
taatatcaga caaaaagcag attagagcaa ttttcttttt cgagttcaaa 60atgggttata
aagcagcgga gacaaaccgc aacatcacca acgcctttgg cccaggaact
120gctaatgaag gtacagtgca gtcactgttc aggaagtttt gcaaaggaga
ctagagcctt 180gaagatgagg agcatagtga ccagccattg gaagtcgaca
aagaccaatt gagaggaatc 240attgaagctg atcatcttac aactacacga
gaagttgtca aagaacgcaa tgttgaccat 300tgtgtggtct tttcgcattt
gaagcaaatt ggaaaggtga aaaacttgat aagtgggtgc 360cttgtgagct
cagcaaaaat ccaaaaaaat aatcattttt aagtgttgtc ttctcttatt
420ctacgcaaca acaataacca ttttgcaatc ggattgtgat gtgcaatgaa
aagtggattt 480ggggccgggc gcggtggctc acgcctgtaa tctcagcact
ttggaaggcc aaggcgggca 540gatcacgagg tcaggagatc aagaccgtcc
tggctaacac ggtgaaaccc cgtctctact 600gaaaatacaa aaaattagcc
gggtgtggtg gctggcgcct gtagtcccag ctacaggctg 660aggcaggaga
atggcatgaa cctgggaggc ggagcttgca gtgagccgag accgtgccac
720tgcactccag cctgggcgac agagcgatac tccgtcaaaa aaaaaaaaaa
aaaaaaaaaa 780agacaagtgg attttatata tggcaaccag caatgaccag
ctcagtggct ggactgagaa 840gaagctccaa agcacttccc aaagccaaac
ttgcaccaaa aaaaaggtca gggtcactgt 900ttggtggtct gctgctggtc
tgatccaccg ctgctctctg aatcctggca aaaccattac 960atctgagaag
tatgctcaac aaatcaatga gctacgccaa aaactgcagc atctgcagct
1020ggcattggtc aacataacgg gtccaattct tctccacgac aacgctcaac
tgcaccttgc 1080gcaagcagcg cttcaaaagt tgaacaaatt gggctacata
gtttttcctc atccgccata 1140ttcacctgac gtcttgccaa ctaactacca
cttcttcaag tatctcaaca actttttgca 1200gggaaaacac ttccacaacc
agcaggatgc agaacacgct ttccaagagt ttgtcgaatc 1260ctgacgcaca
gatttttatg ctacaggaat aaactaactt atttctcatt ggcaaaaatg
1320tgttgattgt aatggttcct attttgatga ataaatgtgt gtttgagcct a
13713238DNAHomo sapiens 3atgctgagcg ccggtcccct gggcccactt
ttctttctct atactttgtc tctgttgtct 60ttcttttctc aagtctctcg ttccacctga
ggagaaatgc ccacagctgt ggaggcgcag 120gccactccat ctggtgccca
acgtggatgc ttttctctag ggtgaaggga ctctcgagtg 180tggtcattga
ggacaagtca acgagagatt cccgagtacg tctacagtga gccttgtg 238479DNAHomo
sapiens 4ggtgaaggta ctctacagtg tggtcattga ggacaagttg acgagagagt
cccaagtacg 60tccacggtca gccttgcgg 79579DNAHomo sapiens 5acatttaaag
ttctacaatg aactcactgg agatgcaaag aaaagtgtgg agatggagac 60accccaatcg
actcgccag 796682DNAHomo sapiens 6tctacaggtg tatccagcag ctccaaagag
acagcaacca gcaagaatgg gccatagtga 60cgatggtggt tttgtcaaaa agaaaagggg
gggatatgta aggaaaagag agatcagact 120ttcactgtgt ctatgtagaa
aaggaagaca taagaaactc cattttgatc tgtactaaga 180aaaattgttt
tgccttgaga tgctgttaat ctgtaacttt agccccaacc ctgtgctcac
240ggaaacatgt gctgtaaggt ttaagggatc tagggctgtg caggatgtac
cttgttaaca 300atatgtttgc aggcagtatg tttggtaaaa gtcatcgcca
ttctccattc tcgattaacc 360aggggctcaa tgcactgtgg aaagccacag
gaacctctgc ccaagaaagc ctggctgttg 420tgggaagtca gggaccccga
atggagggac cagctggtgc tgcatcagga aacataaatt 480gtgaagattt
cttggacatt tatcagtttc caaaattaat acttttataa tttcttacac
540ctgtcttact ttaatctctt aatcctgtta tctttgtaag ctgaggatat
acgtcacctc 600aggaccacta ttgtacaaat tgattgtaaa acatgttcac
atgtgtttga acaatatgaa 660atcagtgcac cttgaaaatg aa 6827238DNAHomo
sapiens 7atgctgagcg ccggtcccct gggcccactt ttctttctct atactttgtc
tctgttgtct 60ttcttttctc aagtctctcg ttccacctga ggagaaatgc ccacagctgt
ggaggcgcag 120gccactccat ctggtgccca acgtggatgc ttttctctag
ggtgaaggga ctctcgagtg 180tggtcattga ggacaagtca acgagagatt
cccgagtacg tctacagtga gccttgtg 23885553DNAHomo sapiens 8tctctcatcc
ctcctgacga gaaataccca caggtgtgga ggggctggcc cccttcatct 60gatgcccaat
gtgggtgcct ttctctaggg tgaaggtact ctacagtgtg gtcattgagg
120acaagttgac gagagagtcc caagtacgtc cacggtcagc cttgcggtaa
gcttgtgtgc 180ttagaggaac ccagggtaac gatggggcaa actgaaagta
aatatgcctc ttatctcagc 240tttattaaaa ttcttttaag aagaggggga
gttagagctt ctacagaaaa tctaattacg 300ctatttcaaa caatagaaca
attctgccca tggtttccag aacagggaac tttagatcta 360aaagattggg
aaaaaattgg caaagaatta aaacaagcaa atagggaagg taaaatcatc
420ccacttacag tatggaatga ttgggccatt attaaagcaa ctttagaacc
atttcaaaca 480ggagaagata ttgtttcagt ttctgatgcc cctaaaagct
gtgtaacaga ttgtgaagaa 540gaggcaggga cagaatccca gcaaggaacg
gaaagttcac attgtaaata tgtagcagag 600tctgtaatgg ctcagtcaac
gcaaaatgtt gactacagtc aattacagga gataatatac 660cctgaatcat
caaaattggg ggaaggaggt ccagaatcat tggggccatc agagcctaaa
720ccacgatcgc catcaactcc tcctcccgtg gttcagatgc ctgtaacatt
acaacctcaa 780acgcaggtta gacaagcaca aaccccaaga gaaaatcaag
tagaaaggga cagagtctct 840atcccggcaa tgccaactca gatacagtat
ccacaatatc agccggtaga aaataagacc 900caaccgctgg tagtttatca
ataccggctg ccaaccgagc ttcagtatcg gcctccttca 960gaggttcaat
acagacctca agcggtgtgt cctgtgccaa atagcacggc accataccag
1020caacccacag cgatggcgtc taattcacca gcaacacagg acgcggcgct
gtatcctcag 1080ccgcccactg tgagacttaa tcctacagca tcacgtagtg
gacagggtgg tgcactgcat 1140gcagtcattg atgaagccag aaaacagggc
gatcttgagg catggcggtt cctggtaatt 1200ttacaactgg tacaggccgg
ggaagagact caagtaggag cgcctgcccg agctgagact 1260agatgtgaac
ctttcaccat gaaaatgtta aaagatataa aggaaggagt taaacaatat
1320ggatccaact ccccttatat aagaacatta ttagattcca ttgctcatgg
aaatagactt 1380actccttatg actgggaaat tttggccaaa tcttcccttt
catcctctca gtatctacag 1440tttaaaacct ggtggattga tggagtacaa
gaacaggtac gaaaaaatca ggctactaag 1500cccactgtta atatagacgc
agaccaattg ttaggaacag gtccaaattg gagcaccatt 1560aaccaacaat
cagtgatgca gaatgaggct attgaacaag taagggctat ttgcctcagg
1620gcctggggaa aaattcagga cccaggaaca gctttcccta ttaattcaat
tagacaaggc 1680tctaaagagc catatcctga ctttgtggca agattacaag
atgctgctca aaagtctatt 1740acagatgaca atgcccgaaa agttattgta
gaattaatgg cctatgaaaa tgcaaatcca 1800gaatgtcagt cggccataaa
gccattaaaa ggaaaagttc cagcaggagt tgatgtaatt 1860acagaatatg
tgaaggcttg tgatgggatt ggaggagcta tgcataaggc aatgctaatg
1920gctcaagcaa tgagggggct cactctagga ggacaagtta gaacatttgg
gaaaaaatgt 1980tataattgtg gtcaaatcgg tcatctgaaa aggagttgcc
caggcttaaa taaacagaat 2040ataataaatc aagctattaa cagcaaaaaa
taaaaagcca tctggcctgt gtccaaaatg 2100tggaaaagca aaacattggg
ccaatcaatg tcattctaaa tttgataaag atgggcaacc 2160attgtctgga
aacaggaaga ggggccagcc tcaggccccc caacaaactg gggcattccc
2220agttaaactg tttgttcctc agggttttca aggacaacaa cccctacaga
aaataccacc 2280acttcaggga gtcagccaat tacaacaatc caacagctgt
cccgcgccac agcaggcagc 2340accgcagtag atttatgttc cacccaaatg
gtctttttac tccctggaaa gcccccacaa 2400aagattccta gaggggtata
tggcccgctg ccagaaggga gggtaggcct ttgagggaga 2460tcgtctaaat
ttgaagggag tccaaattca tactggggta atttattcag attataaagg
2520gggaattcag ttagtgatca gctccactgt tccccggagt gccaatccag
gtgatagaat 2580tgctcaatta ctgcttttgc cttatgttaa aattggggaa
aacaaaaagg aaagaacagg 2640agggtttgga agtaccaacc ctgcaggaaa
agctgcttat tgggctaatc aggtctcaga 2700ggatagaccc gtgtgtacag
tcactattca gggaaagagt ttgaaggatt agtggatacc 2760caggctgatg
tttctgtcat cggcataggt actgcctcag aagtgtatca aagtgccatg
2820attttacatt gtccaggatc tgataatcaa gaaagtacgg ttcagcctgt
gatcacttca 2880ttccaatcaa tttatggggc cgagacttgt tacaacaatg
gcatgcagag attactatcc 2940cagcctccct atacagcccc aggaataaaa
aaatcatgac taaaatggga tagctcccta 3000aaaagggact aggaaagaag
tcccaattga ggctgaaaaa aatcaaaaaa gaaaaggaat 3060agggcatcct
ttttaggagc ggtcactgta gagcctccaa aacccattcc attaacttgg
3120gggaaaaaaa aacaactgta tggtaaatca gcagcgcttc caaaacaaaa
actggaggct 3180ttacatttat tagcaaagaa acaattagaa aaaggacatt
gagccttcat tttcgccttg 3240gaattctgtt tgtaattcag aaaaaatccg
gcagatggcg tataatgccg taattcaacc 3300catgggggct ctcccacccc
ggttgccctc tccagccatg gtccccttta attataattg 3360atctgaagga
ttgctttttt accattcctc tggcaaaaca ggattttgaa aaatttgctt
3420ttaccacacc agcctaaata ataaagaacc agccaccagg tttcagtgga
aagtattgcc 3480tcagggaatg cttaatagtt caactatttg tcagctcaag
ctctgcaacc agttagagac 3540aagttttcag actgttacat cgttcactat
gttgatattt tgtgtgctgc agaaacgaga 3600gacaaattaa ttgaccgtta
cacatttctg cagacagagg ttgccaacgc gggactgaca 3660ataacatctg
ataagattca aacctctact cctttccgtt acttgggaat gcaggtagag
3720gaaaggaaaa ttaaaccaca aaaaatagaa ataagaaaag acacattaaa
agcattaaat 3780gagtttcaaa agttgctagg agatactaat tggatttgga
gatattaatt ggatttggcc 3840aactctaggc attcctactt atgccatgtc
aaatttgttc tctttcttaa gaggggactc 3900ggaattaaat agtgaaagaa
cgttaactcc agaggcaact aaagaaatta aattaattga 3960agaaaaaatt
cggtcagcac aagtaaatag aatagatcac ttggccccac tccaaatttt
4020gatttttgct actgcacatt ccctaacagg catcattgtt caaaatacag
atcttgtgga 4080gtggtccttc cttcctcaca gtacaattaa gacttttaca
ttgtacttgg atcaaatggc 4140tacattaatt ggtcagggaa gattatgaat
aataacattg tgtggaaatg acccagataa 4200aatcactgtt cctttcaaca
agcaacaggt tagacaagcc tttatcaatt ctggtgcatg 4260gcagattggt
cttgccgatt ttgtgggaat tattgacaat cgttacccca aaacaaaaat
4320cttccagttt ttaaaattga ctacttggat tttacctaaa gttaccaaac
ataagccttt 4380aaaaaatgct ctggcagtgt ttactgatgg ttccagcaat
ggaaaagtgg cttacaccgg 4440gccaaaagaa tgagtcatca aaactcagta
tcacttgact caaagagcag agttggttgc 4500cgtcattaca gtgttaacaa
gattttaatc agtctattaa cattgtatca gattctgcat 4560atgtagtaca
ggctacaaag gatattgaga gagccctaat caaatacatt atggatgatc
4620agttaaaccc gctgtttaat ttgttacaac aaaatgtaag aaaaagaaat
ttcccatttt 4680atattactca tattcgagca cacactaatt taccagggcc
tttaactaaa gcaaatgaac 4740aagctgactt gctagtatca tctgcattca
tggaagcaca agaacttcat gccttgactc 4800atgtaaatgc aataggatta
aaaaataaat ttgatatcac atggaaacag acaaaaaata 4860ttgtacaaca
ttgcacccag tgtcagattc tacacctggc cactcaggag gcaagagtta
4920atcccagagg tctatgtcct aatgtgttat ggcaaatgga tgtcatgcac
gtaccttcat 4980ttggaaaatt gtcatttgtc catgtgacag ttgatactta
ttcacatttc atatgggcaa 5040cctgccagac aggagaaagt acttcccatg
ttaaaagaca tttattatct tgttttcctg 5100tcatgggagt tccagaaaaa
gttaaaacag acaatgggcc aggttactgt agtaaagcag 5160ttcaaaaatt
cttaaatcag tggaaaatta cacatacaat aggaattctc tataattccc
5220aaggacaggc cataattgaa agaactaata gaacactcaa agctcaattg
gttaaacaaa 5280aaaaaggaaa agacaggagt ataacactcc ccagatgcaa
cttaatctag cactctatac 5340tttaaatgtt ttaaacattt atagaaatca
gaccactacc tctgcagaac aacatcttac 5400tggtaaaagg aacagcccac
atgaaggaaa actgatttgg tggaaagata ataaaaataa 5460aacatgggaa
atggggaagg tgataacgtg ggggagaggt tttgcttgtg tttcaccagg
5520agaaaatcag cttcctgttt ggatacccac tag 555392179DNAHomo sapiens
9gtaaacaaaa tggtgatatc agaagaacag aaaaagttgc cttccatcaa ggaagcagag
60ttgccaatat aggcacaatt aaagaagctg acacagttag ctaaaaaaaa aagcctagag
120aatacaaagg tgacaccaac tccagagaat atgctgcttg cagctctgat
gattgtatca 180acggtggtaa gtcttcccaa gtctgcagga gcagctgcag
ctaattatac ttactgggcc 240tatgtgcctt tcccaccctt aattcgggca
gttacataga tggataatcc tattgaagta 300gatgttaata atagtgcatg
ggtgcctggc cccacagatg actgttgccc tgcccaacct 360gaagaaggaa
tgatgatgaa tatttccatt gggtatcctt atcctcctgt ttgcctaggg
420aaggcaccag gatgcttaat gcctacaacc caaaattggt tggtagaagt
acctacagtc 480agtgctacca gtagatttac ttatcacatg gtaagtggaa
tgtcacagat aaataattta 540caggaccctt cttatcaaag atcattacaa
tgtaggccta aggggaaggc ttgccccaag 600gaaattccca aagaatcaaa
aagcccagaa gtcttagtct gcggagaatg tgtggctgat 660actgcagtgt
agtacaaaac aatgaatttt gaactatgat agactgggtc ccttgaggcc
720aattatatca taactgtaca ggccagactc attcatgttc acaggcccca
tccatctggc 780ccattaatcc agcctatgac ggtgatgtaa ctgaaaggct
ggaccaggtt tatagaaggt 840tagaatcact ctgtccaagg aaatggggtg
aaaagggaat ttcatcacct tgaccaaagt 900tagtcctgtt actggtcctg
aacatccaga attaggaagc ttactgtggc ctcacaccac 960attagaattt
gttctggaaa tcaagctata ggaacaagag atcgtaagtc atattatact
1020atcaacctaa attccagtct gacaattcct ttgcaaaatt gtgtaaaact
cccttatatt 1080gctagttgta ggaaaaacat agttattaaa cctgattccc
aaaccataat ctgtgaaaat 1140tgtggaatgt ttacttgcat tgatttgact
tttaattggc agcaccgtat tctactagga 1200agagcaagag agggtgtgtg
gatccttgtg tccatggacc gaccatggga ggcttcgcta 1260tccatccata
ttttaacgga agtattaaaa ggaattctaa ctagatccaa aagattcatt
1320tttactttga tggcagtgat tatgggcctc attgcagtca cagctactgc
tgcggctgct 1380ggaattgctt tacactcctc tgttcaaact gcagaatacg
taaatgattg gcaaaagaat 1440tcctcaaaat tgtggaattc tcagatccaa
atagatcaaa aattggcaaa ccaaattaat 1500gatcttagac aaactgtcat
ttggatggga gaggctcatg agcttggaat atctttttca 1560gttacgatgt
gactggaata catcagattt ttgtgttaca ccacaagcct ataatgagtc
1620tgagcatcac tgggacatgg ttagatgcca tctgcaagga ggagaagata
atcttacttt 1680agacatttca aaattaaaag aatttttttt ttctttgaga
cagagtctcg ctctgtcgcc 1740caggctggag tgcagtggcg tgatctcagc
tcactgcaag ttccgcctcc tgggtttaca 1800ccattctcct gcctcagcct
cccaagtagt tgggactaca ggagcccacc accatgcctg 1860gctaattttt
tttgggtttt taatagagat ggagtttcac cgtgttagcc aggatggtct
1920cgatctcctg accttgtgat ctgcccacct tggcctccca aagtgctggg
attacagtcg 1980tgagccaccg tgcccagcca agaaaaaatt tttgaggcat
caaaagccca tttaaatttg 2040gtgccaggaa cggagacaat cgtgaaagct
gctgatagcc tcacaaatct taagccagtc 2100acttgggtta aaagcatcag
aagtttcact attgtaaatt tcatattaat ccttgtatgc 2160ctgttctgtc
tgttgttag 21791016DNAArtificial SequenceSynthetic 10ccgaaccaca
catgga 161118DNAArtificial SequenceSynthetic 11cagatacata aggtaagc
181222DNAArtificial SequenceSynthetic 12tttattttag accatggaaa ta
221332DNAArtificial SequenceSynthetic 13gatgaataaa tgtgtgtttg
agcctagtta tg 3214261DNAArtificial SequenceSynthetic 14cgggtcctcc
atatgctgag cgccggtccc ctgggcccac ttttctttct ctatactttg 60tctctgttgt
ctttcttttc tcaagtctct cgttccacct gaggagaaat gcccacagct
120gtggaggcgc aggccactcc atctggtgcc caacgtggat gcttttctct
agggtgaagg 180gactctcgag tgtggtcatt gaggacaagt caacgagaga
ttcccgagta cgtctacagt 240gagccttgtg gtaagcttgg g
26115101DNAArtificial SequenceSynthetic 15tctttcctca gggtgaaggt
actctacagt gtggtcattg aggacaagtt gacgagagag 60tcccaagtac gtccacggtc
agccttgcgg gtgaaggtac t 10116101DNAArtificial SequenceSynthetic
16atacccacta gacatttaaa gttctacaat gaactcactg gagatgcaaa gaaaagtgtg
60gagatggaga caccccaatc gactcgccag gtaaacaaaa t
10117701DNAArtificial SequenceSynthetic 17tgttgttagt ctacaggtgt
atccagcagc tccaaagaga cagcaaccag caagaatggg 60ccatagtgac gatggtggtt
ttgtcaaaaa gaaaaggggg ggatatgtaa ggaaaagaga 120gatcagactt
tcactgtgtc tatgtagaaa aggaagacat aagaaactcc attttgatct
180gtactaagaa aaattgtttt gccttgagat gctgttaatc tgtaacttta
gccccaaccc 240tgtgctcacg gaaacatgtg ctgtaaggtt taagggatct
agggctgtgc aggatgtacc 300ttgttaacaa tatgtttgca ggcagtatgt
ttggtaaaag tcatcgccat tctccattct 360cgattaacca ggggctcaat
gcactgtgga aagccacagg aacctctgcc caagaaagcc 420tggctgttgt
gggaagtcag ggaccccgaa tggagggacc agctggtgct gcatcaggaa
480acataaattg tgaagatttc ttggacattt atcagtttcc aaaattaata
cttttataat 540ttcttacacc tgtcttactt taatctctta atcctgttat
ctttgtaagc tgaggatata 600cgtcacctca ggaccactat tgtacaaatt
gattgtaaaa catgttcaca tgtgtttgaa 660caatatgaaa tcagtgcacc
ttgaaaatga acagaataac a 70118644DNAArtificial SequenceSynthetic
18ggctccgaac acacatggat attggatatc tgcataggca gcttgctcca cgccagtgcc
60tacctgtgca gatgggaagg aaaggaaagt ggcaaggagg cagagaaagc atctgtaccc
120ttacaatttg gtgagacaag aatgtatgaa ttcccacagg tcaaattata
atgaagaaag 180gaacctctct tgagtacaaa gagctaccta tggtggtctg
gagccggagg accacagcat 240caaaggatat aagatgcata gccaactgag
gaacctgagc aattaaagag atccacagtt 300aagtcacact taactggcac
ttgtggaagc cccgcaaggc ctgaaggaga gctgacatag 360gcaccccgga
gagccagaat ctggatccca tcttaataag gccatgaaca ccagtggaga
420agaggcagaa acaccaatgg ataaggaaca ttcacatctt tcttcccatg
tgcctctaag 480tgccagtgca ggccccacag gccaagctac agggagaaag
gagatgacgc aaaggaacct 540aactggactt taatcactag aagtgagaag
agaaatctat tggaacctcc caagataatg 600ccaagggtca aagggtgcgc
agatacataa ggtaagccct tcgg 644191376DNAArtificial SequenceSynthetic
19tttagaccat ggaaataata tcagacaaaa agcagattag agcaattttc tttttcgagt
60tcaaaatggg ttataaagca gcggagacaa accgcaacat caccaacgcc tttggcccag
120gaactgctaa tgaaggtaca gtgcagtcac tgttcaggaa gttttgcaaa
ggagactaga 180gccttgaaga tgaggagcat agtgaccagc cattggaagt
cgacaaagac caattgagag 240gaatcattga agctgatcat cttacaacta
cacgagaagt tgtcaaagaa cgcaatgttg 300accattgtgt ggtcttttcg
catttgaagc aaattggaaa ggtgaaaaac ttgataagtg 360ggtgccttgt
gagctcagca aaaatccaaa aaaataatca tttttaagtg ttgtcttctc
420ttattctacg caacaacaat aaccattttg caatcggatt gtgatgtgca
atgaaaagtg 480gatttggggc cgggcgcggt ggctcacgcc tgtaatctca
gcactttgga aggccaaggc 540gggcagatca cgaggtcagg agatcaagac
cgtcctggct aacacggtga aaccccgtct 600ctactgaaaa tacaaaaaat
tagccgggtg tggtggctgg cgcctgtagt cccagctaca 660ggctgaggca
ggagaatggc atgaacctgg gaggcggagc ttgcagtgag ccgagaccgt
720gccactgcac tccagcctgg gcgacagagc gatactccgt caaaaaaaaa
aaaaaaaaaa 780aaaaaagaca agtggatttt atatatggca accagcaatg
accagctcag tggctggact 840gagaagaagc tccaaagcac ttcccaaagc
caaacttgca ccaaaaaaaa ggtcagggtc 900actgtttggt ggtctgctgc
tggtctgatc caccgctgct ctctgaatcc tggcaaaacc 960attacatctg
agaagtatgc tcaacaaatc aatgagctac gccaaaaact gcagcatctg
1020cagctggcat tggtcaacat
aacgggtcca attcttctcc acgacaacgc tcaactgcac 1080cttgcgcaag
cagcgcttca aaagttgaac aaattgggct acatagtttt tcctcatccg
1140ccatattcac ctgacgtctt gccaactaac taccacttct tcaagtatct
caacaacttt 1200ttgcagggaa aacacttcca caaccagcag gatgcagaac
acgctttcca agagtttgtc 1260gaatcctgac gcacagattt ttatgctaca
ggaataaact aacttatttc tcattggcaa 1320aaatgtgttg attgtaatgg
ttcctatttt gatgaataaa tgtgtgtttg agccta 137620813DNAHomo sapiens
20tttctcaggt ctggatgtag ggttagatgc cagttagata taagtgaaat agccggttta
60cttaccaata gacaggaaag tagtcttttg tgattccctt ctccactaaa tacaaatcag
120tgctactcag gggctcttta aagaaggagt tggccaggtg tggtgactca
cgcctgtaat 180cttagcactt tgggaggttg aggcgggtgg atcacctgag
gtcaggagtt cgagaccatt 240cctgaccaac atggagaaac cctgtctcta
aaaatacaaa atcagctggg cgtggtggcg 300catgcctgta atcccagcta
cttgggaggc tgaggcagga gaatcgcttg aacccgggag 360gcggaggttg
tagtgagccg agattgtgcc attgcactcc agcctgggca acaagagcga
420aactccgact acatgtaccc taaaacttaa agtataataa taataaaatt
aaaaaaaaaa 480aaaaagaaca gcagcagtaa aaaataaata aagaaataaa
taaataaata aatgaagaag 540tcaatcggta ccataagaaa ggacaaaaac
caaaacaaac ccaaagcaaa accaaaaact 600ccccacaaac cagcctcccc
taaccctttt aactcaaagc ttcgtaatgt ctctgaattt 660ataattacga
ttttaaagag cactgtttct catgccccat cccccaaccc atttcgggag
720taaacctttt ctgtcagggt gaggagaaag tgggtaaagg acttcagcat
ttacagttga 780gttagtattt gttgttctcc aaatgtgcag gaa 81321404DNAHomo
sapiens 21tccttggtgg cttagggtac agttattaat gctggctgtg atgaagtttt
gctggggacc 60aggataacag atggtccagt catggggcct cagtggtggc agtgattagc
tgatcatgcc 120tgtcctttgg ccccaggttg gcttatgctg gcacttgtgt
tgttaggccc aagcagtctg 180atttgggggc ctccacatgg tttgctggga
tgttggtagt ttctgcttcc tggcctgatg 240tggtacatct gggtgagtgc
cagctctggt ggtattagca tgttatgtca gcctgtcctt 300agaccctggg
agaagtgttc atgtgccaat ggtggtagac tgtgctgagt gatttccagg
360cccctggaca gcatactgaa ttactgagag gatgggactg agca
40422362DNAArtificial SequenceSynthetic 22tgggtccaca ctgcttttat
gagctgtaac actcaccgcg aaggtccgca gcttcactcc 60tgaagccagc gagaccacga
gcctactggg aggaacgaac aactcccgac gcgccgcctt 120aagagctgta
acactcaccg cgaaggtctg cagcttcact cctgagccag cgagaccacg
180aacccaccag aaggaaaaaa ctccgaacac atctgaacat cagaagcaac
aaactccgga 240cacgccgcct ttaagaactg taacactcac tgcgagggtc
cgcggcttca ttcttgaagt 300gagtgagacc aagaacccac cagttctgga
cacaatttca agtcctcagg gtgagttttc 360cc 36223124DNAArtificial
SequenceSynthetic 23ctgtgttttc ttttcagtgc catcaatatt ctgaaaatgg
cagtgatttt tattcaacct 60gtataaggca ctttcaccat gtacctggaa gcaacatcta
catctttttc aggtaatagt 120ttcc 12424129DNAArtificial
SequenceSynthetic 24tcaaccacat tcctagtttt cctctgtcca ctatgaagga
ctttgtgacc acattctgac 60tctgatgaga tcctgcccag aattgacctg aaccccaata
attcaccttt ctctcaggta 120atgttttca 12925170DNAArtificial
SequenceSynthetic 25gtttcttctt ctttcagttt cttctacgcc aggtgtgtgc
ttagctccat gacaaaaggt 60gacagcttat tctgcagcac acacacatca tcaaagtggg
aggtggtgag actggcacac 120tgacagtctg tcctagcaga tttcagctca
cactggtgag ttccagcatg 17026294DNAArtificial SequenceSynthetic
26ccctacaatg taacagcaat ctagatgctg gggacacaag gtccaccttc caggaatatg
60gccatgacac cagaaatcac aaacatgatg agaatggaat gactggggaa gaagtgccag
120atgcttcact tgtaaatgaa gacccagcct ctggggatgc agataccacc
tccctgaaga 180agctgaatat ctgcagataa gtggagttca ccaatgatga
ggagcgggat ggagaaagga 240ggtagggaga gtcatccaag gaacatgagc
aacatgttaa aaggtaagaa gtga 29427100DNAArtificial SequenceSynthetic
27tctctactct actctagcca agtggtttaa tttctggaga tggtgaaccc aagaggctct
60gctgggagac aacaaaaata atgaaggtaa tggatgaaar 10028697DNAArtificial
SequenceSynthetic 28acaattgcct tcctagaatt gaaccagagt ccggtgaata
tcagcactgg gaccagttag 60cagaggaaaa ggaaagaata aaagcgaaaa gaatgaagag
tcatatgatt accaactttt 120cctttttcat ataaattgag tgtatatggg
tctggaacaa cctgaatttc catcaagtcc 180tggctaacct cattatgtcc
tatgaatatt tttgactaat cccactttac attaatctgt 240attgtgaatg
tggatattga attatatttc tttgtaatcc cattatccaa aatccagttc
300agagactatt agttaccaat gttcactgtg aaggaaaaaa aaaaaaaaaa
agctcagagg 360ataaacatgt gatatggttt ggctgtgtcc ccacccaaat
atcatcttga attgtagctc 420ccataattcc cacgtgttgt gggagggacc
cggtgggaga taattgtatc atgggggtgg 480ttcccccata ctattctcat
agtagtgaat aagtctcaca aaatctgatg gttttatgag 540ggaaaacccc
tttcacctgg ttctcattct cttctctggt ctgtcgtcat gtaagacatg
600cctttcacct tctccaccat gactgtgagg cctccccagc cacgtggaac
tgtgagccca 660ttaaacctct ttcacttata aattacccag tctctgg 697
* * * * *