Grant Number:	5P01CA228696-05 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:	2024

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.




Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.
Authors: Diossy M. , Tisza V. , Li H. , Sahgal P. , Zhou J. , Sztupinszki Z. , Young D. , Nousome D. , Kuo C. , Jiang J. , et al. .
Source: Npj Precision Oncology, 2024-09-19 00:00:00.0; 8(1), p. 208.
EPub date: 2024-09-19 00:00:00.0.
PMID: 39294262
Related Citations

Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.
Authors: Lenis A.T. , Ravichandran V. , Brown S. , Alam S.M. , Katims A. , Truong H. , Reisz P.A. , Vasselman S. , Nweji B. , Autio K.A. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2024-09-03 00:00:00.0; 30(17), p. 3894-3903.
PMID: 38949888
Related Citations

RAD21 promotes oncogenesis and lethal progression of prostate cancer.
Authors: Su X.A. , Stopsack K.H. , Schmidt D.R. , Ma D. , Li Z. , Scheet P.A. , Penney K.L. , Lotan T.L. , Abida W. , DeArment E.G. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2024-09-03 00:00:00.0; 121(36), p. e2405543121.
EPub date: 2024-08-27 00:00:00.0.
PMID: 39190349
Related Citations

Histopathology and proteomics are synergistic for High-Grade Serous Ovarian Cancer platinum response prediction.
Authors: Kilim O. , Olar A. , Biricz A. , Madaras L. , Pollner P. , Szállási Z. , Sztupinszki Z. , Csabai I. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2024-06-03 00:00:00.0; , .
EPub date: 2024-06-03 00:00:00.0.
PMID: 38883738
Related Citations

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.
Authors: Mitchell J. , Camacho N. , Shea P. , Stopsack K.H. , Joseph V. , Burren O. , Dhindsa R. , Nag A. , Berchuck J.E. , O'Neill A. , et al. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2024-05-10 00:00:00.0; , .
EPub date: 2024-05-10 00:00:00.0.
PMID: 38766261
Related Citations

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer.
Authors: Rumpf F. , Plym A. , Vaselkiv J.B. , Penney K.L. , Preston M.A. , Kibel A.S. , Mucci L.A. , Salari K. .
Source: The Journal Of Urology, 2024-04-10 00:00:00.0; , p. 101097JU0000000000003927.
EPub date: 2024-04-10 00:00:00.0.
PMID: 38598641
Related Citations

Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency.
Authors: Szallasi Z. , Diossy M. , Tisza V. , Li H. , Sahgal P. , Zhou J. , Sztupinszki Z. , Young D. , Nuosome D. , Kuo C. , et al. .
Source: Research Square, 2024-04-01 00:00:00.0; , .
EPub date: 2024-04-01 00:00:00.0.
PMID: 38645014
Related Citations

ATM deficiency confers specific therapeutic vulnerabilities in bladder cancer.
Authors: Zhou Y. , Börcsök J. , Adib E. , Kamran S.C. , Neil A.J. , Stawiski K. , Freeman D. , Stormoen D.R. , Sztupinszki Z. , Samant A. , et al. .
Source: Science Advances, 2023-11-24 00:00:00.0; 9(47), p. eadg2263.
EPub date: 2023-11-22 00:00:00.0.
PMID: 37992168
Related Citations

Liquid biopsy epigenomic profiling for cancer subtyping.
Authors: Baca S.C. , Seo J.H. , Davidsohn M.P. , Fortunato B. , Semaan K. , Sotudian S. , Lakshminarayanan G. , Diossy M. , Qiu X. , El Zarif T. , et al. .
Source: Nature Medicine, 2023 Nov; 29(11), p. 2737-2741.
EPub date: 2023-10-21 00:00:00.0.
PMID: 37865722
Related Citations

Family history of prostate and breast cancer integrated with a polygenic risk score identifies men at highest risk of dying from prostate cancer before age 75 years.
Authors: Plym A. , Zhang Y. , Stopsack K.H. , Jee Y.H. , Wiklund F. , Kibel A.S. , Kraft P. , Giovannucci E. , Penney K.L. , Mucci L.A. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2022-09-14 00:00:00.0; , .
EPub date: 2022-09-14 00:00:00.0.
PMID: 36103261
Related Citations

The Impact of PIK3R1 Mutations and Insulin-PI3K-Glycolytic Pathway Regulation in Prostate Cancer.
Authors: Chakraborty G. , Nandakumar S. , Hirani R. , Nguyen B. , Stopsack K.H. , Kreitzer C. , Rajanala S.H. , Ghale R. , Mazzu Y.Z. , Pillarsetty N.V.K. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2022-08-15 00:00:00.0; 28(16), p. 3603-3617.
PMID: 35670774
Related Citations

PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer.
Authors: Dillon K.M. , Bekele R.T. , Sztupinszki Z. , Hanlon T. , Rafiei S. , Szallasi Z. , Choudhury A.D. , Mouw K.W. .
Source: Npj Precision Oncology, 2022-06-29 00:00:00.0; 6(1), p. 49.
EPub date: 2022-06-29 00:00:00.0.
PMID: 35768576
Related Citations

Clinical annotations for prostate cancer research: Defining data elements, creating a reproducible analytical pipeline, and assessing data quality.
Authors: Keegan N.M. , Vasselman S.E. , Barnett E.S. , Nweji B. , Carbone E.A. , Blum A. , Morris M.J. , Rathkopf D.E. , Slovin S.F. , Danila D.C. , et al. .
Source: The Prostate, 2022-05-10 00:00:00.0; , .
EPub date: 2022-05-10 00:00:00.0.
PMID: 35538298
Related Citations

DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men.
Authors: Plym A. , Dióssy M. , Szallasi Z. , Sartor O. , Silberstein J. , Powell I.J. , Rebbeck T.R. , Penney K.L. , Mucci L.A. , Pomerantz M.M. , et al. .
Source: Jnci Cancer Spectrum, 2022 02; 6(1), .
EPub date: 2021-12-27 00:00:00.0.
PMID: 35079693
Related Citations

p53 Immunohistochemistry to Identify Very High-risk Primary Prostate Cancer: A Prospective Cohort Study with Three Decades of Follow-up.
Authors: Stopsack K.H. , Salles D.C. , Vaselkiv J.B. , Grob S.T. , Mucci L.A. , Lotan T.L. .
Source: European Urology Oncology, 2021-12-27 00:00:00.0; , .
EPub date: 2021-12-27 00:00:00.0.
PMID: 34969655
Related Citations

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 00:00:00.0; , .
EPub date: 2021-10-19 00:00:00.0.
PMID: 34667026
Related Citations

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 00:00:00.0; 12(1), p. 3770.
EPub date: 2021-06-18 00:00:00.0.
PMID: 34145282
Related Citations

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 00:00:00.0; 27(6), p. 1792-1806.
EPub date: 2020-12-17 00:00:00.0.
PMID: 33334906
Related Citations

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 00:00:00.0; 41(7), p. 904-908.
PMID: 32556091
Related Citations

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 00:00:00.0; 26(13), p. 3230-3238.
EPub date: 2020-03-27 00:00:00.0.
PMID: 32220891
Related Citations

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 00:00:00.0; 26(11), p. 2673-2680.
EPub date: 2020-02-18 00:00:00.0.
PMID: 32071115
Related Citations

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 00:00:00.0.
PMID: 32276929
Related Citations

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, 2020-04-19 00:00:00.0; , .
EPub date: 2020-04-19 00:00:00.0.
PMID: 32317181
Related Citations

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 00:00:00.0; 26(8), p. 2047-2064.
EPub date: 2019-12-03 00:00:00.0.
PMID: 31796516
Related Citations

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 00:00:00.0.
PMID: 32856010
Related Citations

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 00:00:00.0; 25(14), p. 4480-4492.
EPub date: 2019-04-17 00:00:00.0.
PMID: 30996073
Related Citations

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 00:00:00.0; 116(23), p. 11390-11395.
EPub date: 2019-05-13 00:00:00.0.
PMID: 31085648
Related Citations