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Grant Details

Grant Number: 5P01CA228696-02 Interpret this number
Primary Investigator: Offit, Kenneth
Organization: Sloan-Kettering Inst Can Research
Project Title: The Impact of DNA Damage Repair Abnormalities in Prostate Cancer
Fiscal Year: 2021


Abstract

SUMMARY/ABSTRACT Prostate cancer is the most commonly diagnosed cancer among men in the United States, with an anticipated 164,690 men being diagnosed in 2018. It is also one of the leading causes of cancer death, with approximately 29,430 deaths anticipated in 2018, usually as a result of metastatic castration-resistant prostate cancer (mCRPC). Pathogenic variants in DNA damage repair (DDR) pathway genes are prevalent in a substantial subset of men who develop mCRPC. These germline or somatic genetic abnormalities, primarily insertions and deletions resulting in protein truncations that interfere with DDR, occur in 20-25% of men with mCRPC. While several studies are underway to leverage these findings for men at the latest stages of prostate cancer, genetic variation in the DDR pathway has not yet been fully characterized for men with localized prostate cancer. While there is increasing evidence that some DDR gene aberrations may be associated with aggressive prostate cancer, this also has not been fully characterized. In the United States, where prostate cancer screening is common, over 90% of patients present initially with localized disease. It is at this point in the natural history of the disease when intervention can have the most profound impact. Thus, a major focus of this proposal is understanding the spectrum of DDR gene aberrations that promote aggressive cancers, particularly in men with high-risk localized and oligometastatic disease. Retrospective series demonstrate that DDR variants occur with low frequency in men with low-risk prostate cancer and with higher frequency in men with high-risk localized prostate cancer. This has wide-ranging clinical implications. For instance, mutational status could be used to identify those at highest risk of developing lethal prostate cancer, and therapy could be optimized based on tumor or germline findings. In addition, targeted screening could be implemented to identify those at highest risk of aggressive disease and provide an opportunity for early intervention. The overarching goal of this program is to increase our understanding of the spectrum of DDR gene aberrations that are associated with adverse outcomes in high-risk localized and oligometastatic prostate cancer. This will allow us to optimize the therapeutic approach to patients who have DDR aberrations, to detect and treat lethal disease early, and to improve outcomes for patients and their relatives who carry germline aberrations. In order to achieve our goal, we have assembled a multi-institutional and multidisciplinary group of investigators, including clinical investigators, epidemiologists, statisticians, pathologists, clinical geneticists, computational biologists, bioinformaticians, and basic scientists. Our specific aims are to determine the association between long-term clinical outcome and pathogenic germline and somatic variants in DDR genes across different ethnic groups, to develop treatment strategies for patients with germline or somatic alterations in DDR pathways, and to evaluate the functional significance of different alterations in DDR genes.



Publications

Differences in prostate cancer genomes by self-reported race: Contributions of genetic ancestry, modifiable cancer risk factors, and clinical factors.
Authors: Stopsack K.H. , Nandakumar S. , Arora K. , Nguyen B. , Vasselman S.E. , Nweji B. , McBride S.M. , Morris M.J. , Rathkopf D.E. , Slovin S.F. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2021-10-19; , .
EPub date: 2021-10-19.
PMID: 34667026
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Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS.
Authors: Rose Brannon A. , Jayakumaran G. , Diosdado M. , Patel J. , Razumova A. , Hu Y. , Meng F. , Haque M. , Sadowska J. , Murphy B.J. , et al. .
Source: Nature communications, 2021-06-18; 12(1), p. 3770.
EPub date: 2021-06-18.
PMID: 34145282
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Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in BRCA2-altered Prostate Tumors.
Authors: Chakraborty G. , Patail N.K. , Hirani R. , Nandakumar S. , Mazzu Y.Z. , Yoshikawa Y. , Atiq M. , Jehane L.E. , Stopsack K.H. , Lee G.M. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2021-03-15; 27(6), p. 1792-1806.
EPub date: 2020-12-17.
PMID: 33334906
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Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics.
Authors: Nguyen B. , Mota J.M. , Nandakumar S. , Stopsack K.H. , Weg E. , Rathkopf D. , Morris M.J. , Scher H.I. , Kantoff P.W. , Gopalan A. , et al. .
Source: European urology, 2020 11; 78(5), p. 671-679.
EPub date: 2020-04-19.
PMID: 32317181
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Tumor protein expression of the DNA repair gene BRCA1 and lethal prostate cancer.
Authors: Stopsack K.H. , Gerke T. , Zareba P. , Pettersson A. , Chowdhury D. , Ebot E.M. , Flavin R. , Finn S. , Kantoff P.W. , Stampfer M.J. , et al. .
Source: Carcinogenesis, 2020-07-14; 41(7), p. 904-908.
PMID: 32556091
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Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer.
Authors: Stopsack K.H. , Nandakumar S. , Wibmer A.G. , Haywood S. , Weg E.S. , Barnett E.S. , Kim C.J. , Carbone E.A. , Vasselman S.E. , Nguyen B. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-07-01; 26(13), p. 3230-3238.
EPub date: 2020-03-27.
PMID: 32220891
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TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention?
Authors: Stopsack K.H. , Mucci L.A. , Antonarakis E.S. , Nelson P.S. , Kantoff P.W. .
Source: Cancer discovery, 2020 06; 10(6), p. 779-782.
EPub date: 2020-04-10.
PMID: 32276929
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Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations.
Authors: Sztupinszki Z. , Diossy M. , Krzystanek M. , Borcsok J. , Pomerantz M.M. , Tisza V. , Spisak S. , Rusz O. , Csabai I. , Freedman M.L. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-06-01; 26(11), p. 2673-2680.
EPub date: 2020-02-18.
PMID: 32071115
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Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression.
Authors: Chakraborty G. , Armenia J. , Mazzu Y.Z. , Nandakumar S. , Stopsack K.H. , Atiq M.O. , Komura K. , Jehane L. , Hirani R. , Chadalavada K. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-04-15; 26(8), p. 2047-2064.
EPub date: 2019-12-03.
PMID: 31796516
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Platinum-Based Chemotherapy in Metastatic Prostate Cancer With DNA Repair Gene Alterations.
Authors: Mota J.M. , Barnett E. , Nauseef J.T. , Nguyen B. , Stopsack K.H. , Wibmer A. , Flynn J.R. , Heller G. , Danila D.C. , Rathkopf D. , et al. .
Source: JCO precision oncology, 2020; 4, p. 355-366.
EPub date: 2020-04-16.
PMID: 32856010
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A Novel Mechanism Driving Poor-Prognosis Prostate Cancer: Overexpression of the DNA Repair Gene, Ribonucleotide Reductase Small Subunit M2 (RRM2).
Authors: Mazzu Y.Z. , Armenia J. , Chakraborty G. , Yoshikawa Y. , Coggins S.A. , Nandakumar S. , Gerke T.A. , Pomerantz M.M. , Qiu X. , Zhao H. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2019-07-15; 25(14), p. 4480-4492.
EPub date: 2019-04-17.
PMID: 30996073
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Aneuploidy drives lethal progression in prostate cancer.
Authors: Stopsack K.H. , Whittaker C.A. , Gerke T.A. , Loda M. , Kantoff P.W. , Mucci L.A. , Amon A. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2019-06-04; 116(23), p. 11390-11395.
EPub date: 2019-05-13.
PMID: 31085648
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