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Grant Details

Grant Number: 5R01CA251555-02 Interpret this number
Primary Investigator: Freedman, Matthew
Organization: Dana-Farber Cancer Inst
Project Title: Elucidation of the Genetic Mechanisms Driving Prostate Tumorigenesis Through Integrative Computational and Functional Approaches
Fiscal Year: 2022


Abstract

PROJECT SUMMARY/ABSTRACT Although genome-wide association studies (GWAS) have been extremely successful in identifying numerous germline variants associated to risk for prostate cancer, the causal mechanism between genetic variation and disease risk remains largely unknown at the vast majority of these loci. This prohibits the full realization of novel drug targets and/or personalized treatments. In the quest to address this gap, post-GWAS studies are experiencing a “big data” revolution driven by the exponentially decreasing costs of high-throughput genomic assays. Multiple layers of data (genetic variation, transcriptome levels, epigenetic modifications, localization of tissue-specific regulatory sites, 3D interactions, etc.) are routinely collected in increasingly large cohorts of individuals. This raises the need for rigorous computational and experimental frameworks that integrate various types of data to identify and validate causal genes and variants in prostate cancer. Here we propose a rigorous framework aimed at loci where risk is mediated through alteration in gene expression levels. We deliberately and exhaustively propose to examine all risk loci for prostate cancer to prioritize causal variants and genes and to functionally validate them in prostate cancer tissue and cell lines.



Publications

Best practices for multi-ancestry, meta-analytic transcriptome-wide association studies: Lessons from the Global Biobank Meta-analysis Initiative.
Authors: Bhattacharya A. , Hirbo J.B. , Zhou D. , Zhou W. , Zheng J. , Kanai M. , Global Biobank Meta-analysis Initiative , Pasaniuc B. , Gamazon E.R. , Cox N.J. .
Source: Cell genomics, 2022-10-12; 2(10), .
PMID: 36341024
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Patterns of structural variation define prostate cancer across disease states.
Authors: Zhou M. , Ko M. , Hoge A.C. , Luu K. , Liu Y. , Russell M.L. , Hannon W.W. , Zhang Z. , Carrot-Zhang J. , Beroukhim R. , et al. .
Source: JCI insight, 2022-09-08; 7(17), .
EPub date: 2022-09-08.
PMID: 35943799
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Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.
Authors: Berchuck J.E. , Boiarsky D. , Silver R. , Sunkara R. , McClure H.M. , Tsai H.K. , Siegmund S. , Tewari A.K. , Nowak J.A. , Lindeman N.I. , et al. .
Source: JCO precision oncology, 2022 Aug; 6, p. e2200329.
PMID: 36103646
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Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.
Authors: Qiu X. , Brown L.G. , Conner J.L. , Nguyen H.M. , Boufaied N. , Abou Alaiwi S. , Seo J.H. , El Zarif T. , Bell C. , O'Connor E. , et al. .
Source: JCI insight, 2022-05-23; 7(10), .
EPub date: 2022-05-23.
PMID: 35603787
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HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer.
Authors: Lu X. , Fong K.W. , Gritsina G. , Wang F. , Baca S.C. , Brea L.T. , Berchuck J.E. , Spisak S. , Ross J. , Morrissey C. , et al. .
Source: Nature genetics, 2022 May; 54(5), p. 670-683.
EPub date: 2022-04-25.
PMID: 35468964
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A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.
Authors: Mortlock S. , Corona R.I. , Kho P.F. , Pharoah P. , Seo J.H. , Freedman M.L. , Gayther S.A. , Siedhoff M.T. , Rogers P.A.W. , Leuchter R. , et al. .
Source: Cell reports. Medicine, 2022-03-15; 3(3), p. 100542.
EPub date: 2022-03-15.
PMID: 35492879
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Fast estimation of genetic correlation for biobank-scale data.
Authors: Wu Y. , Burch K.S. , Ganna A. , Pajukanta P. , Pasaniuc B. , Sankararaman S. .
Source: American journal of human genetics, 2022-01-06; 109(1), p. 24-32.
EPub date: 2021-12-02.
PMID: 34861179
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Androgen receptor and MYC equilibration centralizes on developmental super-enhancer.
Authors: Guo H. , Wu Y. , Nouri M. , Spisak S. , Russo J.W. , Sowalsky A.G. , Pomerantz M.M. , Wei Z. , Korthauer K. , Seo J.H. , et al. .
Source: Nature communications, 2021-12-15; 12(1), p. 7308.
EPub date: 2021-12-15.
PMID: 34911936
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H3K27ac HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility.
Authors: Giambartolomei C. , Seo J.H. , Schwarz T. , Freund M.K. , Johnson R.D. , Spisak S. , Baca S.C. , Gusev A. , Mancuso N. , Pasaniuc B. , et al. .
Source: American journal of human genetics, 2021-12-02; 108(12), p. 2284-2300.
EPub date: 2021-11-24.
PMID: 34822763
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