Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

ABSTRACT: BACKGROUND:Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE:To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS:Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS:Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ?4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS:Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY:Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

SUBMITTER: Carter HB 

PROVIDER: S-EPMC6699614 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature