Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.

Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa).

To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden.

A cross-sectional study of 2391 localized PrCa patients was carried out.

Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males.

AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort.

DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing.

In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.

European urology. 2021 Oct 25 [Epub ahead of print]

Daniel J Lee, Ryan Hausler, Anh N Le, Gregory Kelly, Jacquelyn Powers, James Ding, Emily Feld, Heena Desai, Casey Morrison, Abigail Doucette, Peter Gabriel, Regeneron Genetics Center, Renae L Judy, Joellen Weaver, Rachel Kember, Scott M Damrauer, Daniel J Rader, Susan M Domchek, Vivek Narayan, Lauren E Schwartz, Kara N Maxwell

Department of Surgery, Division of Urology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Regeneron Genetics Center, Tarrytown, NY, USA., Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Surgery, Division of Vascular Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA., Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. Electronic address: .

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