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Grant Details

Grant Number: 5R01CA132874-04 Interpret this number
Primary Investigator: Chinnaiyan, Arul
Organization: University Of Michigan
Project Title: Molecuar Sub-Typing of Prostate Cancer Based on Recurrent Gene Fusions
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Employing a bioinformatics approach to analyze prostate cancer gene expression profiles, we identified recurrent gene fusions/translocations in the majority of prostate cancers (Tomlins et al, Science 2005). Specifically, we identified the androgen regulatory elements of TMPRSS2 fused to the members of the ETS family of transcription factors including ERG, ETV1, ETV4 and ETV5. Analogous to hematological malignancies, gene fusions/translocations identified in prostate cancer may represent pathognomonic biomarkers and molecular sub-types of disease. In this application, we plan to focus our efforts on characterizing this new class of gene fusion biomarkers. Preliminary work done by our group and others suggest that molecular subtypes as well as transcript variants of gene fusions may be associated with clinical sub-types of prostate cancer. The central hypothesis of this application is that molecular sub-types based on gene fusions and variants will be useful predictors of the aggressive potential of clinically localized prostate cancer and thus guide treatment. Given this, we propose the following Aims: Specific Aim 1: Discovery and nomination of novel molecular sub-types of prostate cancer. Specific Aim 2: Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease in a radical prostatectomy cohort. Specific Aim 3. Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease using prostate needle biopsy samples. PUBLIC HEALTH RELEVANCE: Project Narrative: The discovery of genes fused together is a major advancement in the understanding of prostate cancer. This proposal is about using these "gene fusions" to identify prognostic categories to improve approaches to the treatment of prostate cancer patients.

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Publications

The lncRNA PCAT29 Inhibits Oncogenic Phenotypes in Prostate Cancer.
Authors: Malik R, Patel L, Prensner JR, Shi Y, Iyer MK, Subramaniyan S, Carley A, Niknafs YS, Sahu A, Han S, Ma T, Liu M, Asangani IA, Jing X, Cao X, Dhanasekaran SM, Robinson DR, Feng FY, Chinnaiyan AM
Source: Mol Cancer Res, 2014 Aug;12(8), p. 1081-7.
EPub date: 2014 Jul 16.
PMID: 25030374
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Molecular Pathways: Targeting ETS Gene Fusions in Cancer.
Authors: Feng FY, Brenner JC, Hussain M, Chinnaiyan AM
Source: Clin Cancer Res, 2014 Sep 1;20(17), p. 4442-8.
EPub date: 2014 Jun 23.
PMID: 24958807
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HOXB13 G84E-related familial prostate cancers: a clinical, histologic, and molecular survey.
Authors: Smith SC, Palanisamy N, Zuhlke KA, Johnson AM, Siddiqui J, Chinnaiyan AM, Kunju LP, Cooney KA, Tomlins SA
Source: Am J Surg Pathol, 2014 May;38(5), p. 615-26.
PMID: 24722062
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PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer.
Authors: Prensner JR, Chen W, Iyer MK, Cao Q, Ma T, Han S, Sahu A, Malik R, Wilder-Romans K, Navone N, Logothetis CJ, Araujo JC, Pisters LL, Tewari AK, Canman CE, Knudsen KE, Kitabayashi N, Rubin MA, Demichelis F, Lawrence TS, Chinnaiyan AM, Feng FY
Source: Cancer Res, 2014 Mar 15;74(6), p. 1651-60.
EPub date: 2014 Jan 28.
PMID: 24473064
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The central role of EED in the orchestration of polycomb group complexes.
Authors: Cao Q, Wang X, Zhao M, Yang R, Malik R, Qiao Y, Poliakov A, Yocum AK, Li Y, Chen W, Cao X, Jiang X, Dahiya A, Harris C, Feng FY, Kalantry S, Qin ZS, Dhanasekaran SM, Chinnaiyan AM
Source: Nat Commun, 2014;5, p. 3127.
PMID: 24457600
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The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex.
Authors: Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, Vergara IA, Davicioni E, Erho N, Ghadessi M, Jenkins RB, Triche TJ, Malik R, Bedenis R, McGregor N, Ma T, Chen W, Han S, Jing X, Cao X, Wang X, Chandler B, Yan W, Siddiqui J, Kunju LP, Dhanasekaran SM, Pienta KJ, Feng FY, Chinnaiyan AM
Source: Nat Genet, 2013 Nov;45(11), p. 1392-8.
EPub date: 2013 Sep 29.
PMID: 24076601
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Evaluation of tissue PCA3 expression in prostate cancer by RNA in situ hybridization--a correlative study with urine PCA3 and TMPRSS2-ERG.
Authors: Warrick JI, Tomlins SA, Carskadon SL, Young AM, Siddiqui J, Wei JT, Chinnaiyan AM, Kunju LP, Palanisamy N
Source: Mod Pathol, 2014 Apr;27(4), p. 609-20.
EPub date: 2013 Sep 27.
PMID: 24072184
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The role of sarcosine metabolism in prostate cancer progression.
Authors: Khan AP, Rajendiran TM, Ateeq B, Asangani IA, Athanikar JN, Yocum AK, Mehra R, Siddiqui J, Palapattu G, Wei JT, Michailidis G, Sreekumar A, Chinnaiyan AM
Source: Neoplasia, 2013 May;15(5), p. 491-501.
PMID: 23633921
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Advancing precision medicine for prostate cancer through genomics.
Authors: Roychowdhury S, Chinnaiyan AM
Source: J Clin Oncol, 2013 May 20;31(15), p. 1866-73.
EPub date: 2013 Apr 15.
PMID: 23589550
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Identification of targetable FGFR gene fusions in diverse cancers.
Authors: Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM
Source: Cancer Discov, 2013 Jun;3(6), p. 636-47.
EPub date: 2013 Apr 4.
PMID: 23558953
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Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma.
Authors: Bhalla R, Kunju LP, Tomlins SA, Christopherson K, Cortez C, Carskadon S, Siddiqui J, Park K, Mosquera JM, Pestano GA, Rubin MA, Chinnaiyan AM, Palanisamy N
Source: Mod Pathol, 2013 Jun;26(6), p. 835-48.
EPub date: 2013 Jan 25.
PMID: 23348902
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Gene Fusion Markup Language: a prototype for exchanging gene fusion data.
Authors: Kalyana-Sundaram S, Shanmugam A, Chinnaiyan AM
Source: BMC Bioinformatics, 2012 Oct 16;13, p. 269.
EPub date: 2012 Oct 16.
PMID: 23072312
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SLC45A3-ELK4 chimera in prostate cancer: spotlight on cis-splicing.
Authors: Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM
Source: Cancer Discov, 2012 Jul;2(7), p. 582-5.
PMID: 22787087
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Expressed pseudogenes in the transcriptional landscape of human cancers.
Authors: Kalyana-Sundaram S, Kumar-Sinha C, Shankar S, Robinson DR, Wu YM, Cao X, Asangani IA, Kothari V, Prensner JR, Lonigro RJ, Iyer MK, Barrette T, Shanmugam A, Dhanasekaran SM, Palanisamy N, Chinnaiyan AM
Source: Cell, 2012 Jun 22;149(7), p. 1622-34.
PMID: 22726445
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The mutational landscape of lethal castration-resistant prostate cancer.
Authors: Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC, Asangani IA, Ateeq B, Chun SY, Siddiqui J, Sam L, Anstett M, Mehra R, Prensner JR, Palanisamy N, Ryslik GA, Vandin F, Raphael BJ, Kunju LP, Rhodes DR, Pienta KJ, Chinnaiyan AM, Tomlins SA
Source: Nature, 2012 Jul 12;487(7406), p. 239-43.
PMID: 22722839
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From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer.
Authors: Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, Mo F, Zoubeidi A, Anderson S, Bell RH, Haegert A, Shukin R, Wang Y, Fazli L, Hurtado-Coll A, Jones EC, Hach F, Hormozdiari F, Hajirasouliha I, Boutros PC, Bristow RG, Zhao Y, Marra MA, Fanjul A, Maher CA, Chinnaiyan AM, Rubin MA, Beltran H, Sahinalp SC, Gleave ME, Volik SV, Collins CC
Source: J Pathol, 2012 Jul;227(3), p. 286-97.
PMID: 22553170
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Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target.
Authors: Collins CC, Volik SV, Lapuk AV, Wang Y, Gout PW, Wu C, Xue H, Cheng H, Haegert A, Bell RH, Brahmbhatt S, Anderson S, Fazli L, Hurtado-Coll A, Rubin MA, Demichelis F, Beltran H, Hirst M, Marra M, Maher CA, Chinnaiyan AM, Gleave M, Bertino JR, Lubin M, Wang Y
Source: Mol Cancer Ther, 2012 Mar;11(3), p. 775-83.
EPub date: 2012 Jan 17.
PMID: 22252602
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Characterization of KRAS rearrangements in metastatic prostate cancer.
Authors: Wang XS, Shankar S, Dhanasekaran SM, Ateeq B, Sasaki AT, Jing X, Robinson D, Cao Q, Prensner JR, Yocum AK, Wang R, Fries DF, Han B, Asangani IA, Cao X, Li Y, Omenn GS, Pflueger D, Gopalan A, Reuter VE, Kahoud ER, Cantley LC, Rubin MA, Palanisamy N, Varambally S, Chinnaiyan AM
Source: Cancer Discov, 2011 Jun;1(1), p. 35-43.
EPub date: 2011 Jun 1.
PMID: 22140652
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Personalized oncology through integrative high-throughput sequencing: a pilot study.
Authors: Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, Kalyana-Sundaram S, Sam L, Balbin OA, Quist MJ, Barrette T, Everett J, Siddiqui J, Kunju LP, Navone N, Araujo JC, Troncoso P, Logothetis CJ, Innis JW, Smith DC, Lao CD, Kim SY, Roberts JS, Gruber SB, Pienta KJ, Talpaz M, Chinnaiyan AM
Source: Sci Transl Med, 2011 Nov 30;3(111), p. 111ra121.
PMID: 22133722
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Coordinated regulation of polycomb group complexes through microRNAs in cancer.
Authors: Cao Q, Mani RS, Ateeq B, Dhanasekaran SM, Asangani IA, Prensner JR, Kim JH, Brenner JC, Jing X, Cao X, Wang R, Li Y, Dahiya A, Wang L, Pandhi M, Lonigro RJ, Wu YM, Tomlins SA, Palanisamy N, Qin Z, Yu J, Maher CA, Varambally S, Chinnaiyan AM
Source: Cancer Cell, 2011 Aug 16;20(2), p. 187-99.
PMID: 21840484
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Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA.
Authors: Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, Williamsen S, Hodge P, Meinke J, Blase A, Penabella Y, Day JR, Varambally R, Han B, Wood D, Wang L, Sanda MG, Rubin MA, Rhodes DR, Hollenbeck B, Sakamoto K, Silberstein JL, Fradet Y, Amberson JB, Meyers S, Palanisamy N, Rittenhouse H, Wei JT, Groskopf J, Chinnaiyan AM
Source: Sci Transl Med, 2011 Aug 3;3(94), p. 94ra72.
PMID: 21813756
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Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression.
Authors: Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD, Cao X, Jing X, Wang X, Siddiqui J, Wei JT, Robinson D, Iyer HK, Palanisamy N, Maher CA, Chinnaiyan AM
Source: Nat Biotechnol, 2011 Jul 31;29(8), p. 742-9.
EPub date: 2011 Jul 31.
PMID: 21804560
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Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer.
Authors: Kim JH, Dhanasekaran SM, Prensner JR, Cao X, Robinson D, Kalyana-Sundaram S, Huang C, Shankar S, Jing X, Iyer M, Hu M, Sam L, Grasso C, Maher CA, Palanisamy N, Mehra R, Kominsky HD, Siddiqui J, Yu J, Qin ZS, Chinnaiyan AM
Source: Genome Res, 2011 Jul;21(7), p. 1028-41.
PMID: 21724842
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TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers.
Authors: Mani RS, Iyer MK, Cao Q, Brenner JC, Wang L, Ghosh A, Cao X, Lonigro RJ, Tomlins SA, Varambally S, Chinnaiyan AM
Source: Cancer Res, 2011 Aug 15;71(16), p. 5387-92.
EPub date: 2011 Jun 15.
PMID: 21676887
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Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.
Authors: Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H, Yu J, Palanisamy N, Siddiqui J, Yan W, Cao X, Mehra R, Sabolch A, Basrur V, Lonigro RJ, Yang J, Tomlins SA, Maher CA, Elenitoba-Johnson KS, Hussain M, Navone NM, Pienta KJ, Varambally S, Feng FY, Chinnaiyan AM
Source: Cancer Cell, 2011 May 17;19(5), p. 664-78.
PMID: 21575865
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Therapeutic targeting of SPINK1-positive prostate cancer.
Authors: Ateeq B, Tomlins SA, Laxman B, Asangani IA, Cao Q, Cao X, Li Y, Wang X, Feng FY, Pienta KJ, Varambally S, Chinnaiyan AM
Source: Sci Transl Med, 2011 Mar 2;3(72), p. 72ra17.
PMID: 21368222
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Antibody-based detection of ERG rearrangement-positive prostate cancer.
Authors: Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, Suleman K, Varambally S, Brenner JC, MacDonald T, Srivastava A, Tewari AK, Sathyanarayana U, Nagy D, Pestano G, Kunju LP, Demichelis F, Chinnaiyan AM, Rubin MA
Source: Neoplasia, 2010 Jul;12(7), p. 590-8.
PMID: 20651988
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The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer.
Authors: Yu J, Cao Q, Yu J, Wu L, Dallol A, Li J, Chen G, Grasso C, Cao X, Lonigro RJ, Varambally S, Mehra R, Palanisamy N, Wu JY, Latif F, Chinnaiyan AM
Source: Oncogene, 2010 Sep 30;29(39), p. 5370-80.
EPub date: 2010 Jul 12.
PMID: 20622896
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Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma.
Authors: Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, LaFargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM
Source: Nat Med, 2010 Jul;16(7), p. 793-8.
EPub date: 2010 Jun 6.
PMID: 20526349
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An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.
Authors: Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM
Source: Cancer Cell, 2010 May 18;17(5), p. 443-54.
PMID: 20478527
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Induced chromosomal proximity and gene fusions in prostate cancer.
Authors: Mani RS, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N, Chinnaiyan AM
Source: Science, 2009 Nov 27;326(5957), p. 1230.
EPub date: 2009 Oct 29.
PMID: 19933109
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Chimeric transcript discovery by paired-end transcriptome sequencing.
Authors: Maher CA, Palanisamy N, Brenner JC, Cao X, Kalyana-Sundaram S, Luo S, Khrebtukova I, Barrette TR, Grasso C, Yu J, Lonigro RJ, Schroth G, Kumar-Sinha C, Chinnaiyan AM
Source: Proc Natl Acad Sci U S A, 2009 Jul 28;106(30), p. 12353-8.
EPub date: 2009 Jul 10.
PMID: 19592507
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Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression.
Authors: Han B, Mehra R, Lonigro RJ, Wang L, Suleman K, Menon A, Palanisamy N, Tomlins SA, Chinnaiyan AM, Shah RB
Source: Mod Pathol, 2009 Aug;22(8), p. 1083-93.
EPub date: 2009 May 1.
PMID: 19407851
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Oncogenic gene fusions in epithelial carcinomas.
Authors: Prensner JR, Chinnaiyan AM
Source: Curr Opin Genet Dev, 2009 Feb;19(1), p. 82-91.
EPub date: 2009 Feb 21.
PMID: 19233641
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Transcriptome sequencing to detect gene fusions in cancer.
Authors: Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X, Sam L, Barrette T, Palanisamy N, Chinnaiyan AM
Source: Nature, 2009 Mar 5;458(7234), p. 97-101.
EPub date: 2009 Jan 11.
PMID: 19136943
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