Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance. (25th April 2022)

• Record Type: Journal Article
• Authors: Brady, Lauren; Newcomb, Lisa F.; Zhu, Kehao; Zheng, Yingye; Boyer, Hilary; Sarkar, Navonil De; McKenney, Jesse K.; Brooks, James D.; Carroll, Peter R.; Dash, Atreya; Ellis, William J.; Filson, Christopher P.; Gleave, Martin E.; Liss, Michael A.; Martin, Frances; Morgan, Todd M.; Thompson, Ian M.; Wagner, Andrew A.; Pritchard, Colin C.; Lin, Daniel W.; Nelson, Peter S.
• Is Part Of: Cancer medicine. Volume 11:Number 22(2022)
• Page Start: 4332
• Page End: 4340
• Publication Date: 2022-04-25
• Subjects: active surveillance -- adverse pathology -- germline mutations -- prostate cancer; 616.994005
• DOI: 10.1002/cam4.4778
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low‐risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance. Methods: Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively. Results: Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2 . The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36–2.06, p = 0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2 did not differ in men with or without grade reclassification (1.9% vs. 1.8%). Conclusion: The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics. Abstract : Low‐risk prostate cancer is generally managed using active surveillance with deferred aggressive treatment. Pathogenic germline mutations in several rare penetrant cancer predisposition genes such as BRCA2 are associated with an increased risk of aggressive prostate cancer and could influence treatment choice. We ascertained the prevalence of pathogenic mutations in men with low risk prostate cancer enrolled on an active surveillance study. The frequency of pathogenic germline mutations in penetrant cancer predisposition genes was extremely low in men on active surveillance and no association with grade reclassification or adverse characteristics during surveillance or unfavorable outcomes after treatment was identified.