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.
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.
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 BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%).
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.
Cancer medicine. 2022 Apr 25 [Epub ahead of print]
Lauren Brady, Lisa F Newcomb, Kehao Zhu, Yingye Zheng, Hilary Boyer, Navonil De Sarkar, Jesse K McKenney, James D Brooks, Peter R Carroll, Atreya Dash, William J Ellis, Christopher P Filson, Martin E Gleave, Michael A Liss, Frances Martin, Todd M Morgan, Ian M Thompson, Andrew A Wagner, Colin C Pritchard, Daniel W Lin, Peter S Nelson
Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA., Department of Urology, Stanford University, Stanford, California, USA., Department of Urology, University of California, San Francisco, California, USA., VA Puget Sound Health Care Systems, Seattle, WA, USA., Department of Urology, University of Washington, Seattle, Washington, USA., Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA., Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Department of Urology, University of Texas Health Sciences Center, San Antonio, Texas, USA., Department of Urology, Eastern Virginia Medical School, Virginia Beach, Virginia, USA., Department of Urology, University of Michigan, Ann Arbor, Michigan, USA., CHRISTUS Medical Center Hospital, San Antonio, Texas, USA., Division of Urology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.