Associations of BRCA1/2 mutations and polygenic risk score with prostate cancer risk and mortality in a founder population

Introduction : Prostate cancer (PrCa) is the most common solid tumor and the second-leading cause of cancer deaths among U.S. men. Although the multi-factorial etiology of this cancer indicates the involvement of several biological pathways, to date the role of rare vs common genetic variants (SNPs) in risk prediction of more aggressive or fatal PrCa remains unclear. The goal of this project is to examine the associations of rare germline BRCA1/2 mutations and a polygenic risk score (PRS) with risks of total and aggressive PrCa as well as with overall and cancer-specific mortality in a founder population. Methods : Epidemiological and germline genotype data collected from 943 PrCa cases and 1,199 controls of Ashkenazim Jewish descent were used in this analysis. We evaluated associations of BRCA1 (185delAG) and BRCA2 (6174delT) founder mutations and a PRS generated from 77 SNPs with risks of total PrCa and high-grade cancer (defined as Gleason score 7-10) using logistic and multinomial regression models, respectively, and adjusted for age and family history of PrCa. All men were followed for mortality via linkage with the U.S. National Death Index from recruitment into the study (between 1999 and 2003) through 12/31/2022. Cox regression models and competing risk analyses were used to examine associations of BRCA1/2 mutations and PRS with overall and PrCa-specific mortality after adjustment for age, Charlson comorbidity index as well as clinical factors and PrCa treatment. Results : The prevalence of BRCA1 (185delAG: 1.2% vs 0.7% ) and BRCA2 (6174delT: 1.3% vs 0.9% ) were higher in cases vs controls. Mutation carriers of either BRCA1 or BRCA2 mutations had ORs of 1.92 (95%CI 1.00-3.67) for total PrCa and 3.38 (95%CI 1.63-7.04) for high-grade PrCa compared to non-mutation carriers. The PRS score was also independently associated with a statistically significant 2.2 to 2.3-fold higher risk for total PrCa and aggressive cancer. During a median follow-up of 19.7 years a total of 712 out of 943 (76%) men diagnosed with PrCa had died, of whom 124 (17.4%) were PrCa-specific deaths. BRCA2 mutation carriers had hazard ratios (HR) of 1.92 (p=0.008) and 2.88 (p=0.01) for overall and PrCa-specific mortality compared to non-mutation carriers. However, there was no association of the PRS score with PrCa-specific mortality (HR=0.98, p=0.89) and a borderline significant 9% lower risk (HR=0.91, p=0.05) with overall mortality. Conclusion : Carriers of BRCA1 and particularly BRCA2 mutations have increased risks of more aggressive and fatal PrCa. Although the PRS score was associated with overall risk, it did not confer any elevated risk for higher Gleason score tumors or fatal PrCa. Evaluation for BRCA2 mutations might be helpful for risk-stratification of men for PrCa screening and potentially targeted therapy.