Germline sequencing of DNA-damage-repair genes in two hereditary prostate cancer cohorts reveals new disease risk-associated gene variants

Background Knowledge of rare, inherited variants in DNA damage repair (DDR) genes is informing clinical management in common cancers. However, defining the rare disease- associated variants in prostate cancer (PrCa) is challenging due to their low frequency. Method Here, whole-genome and -exome sequencing data from two independent, high- risk Australian and North American familial PrCa datasets were interrogated for novel, rare DDR variants. Segregating, high-risk, likely pathogenic DDR gene variants were identified and subsequently genotyped in 1,963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls) and association analyses performed accounting for relatedness (M QLS ). Results Rare variants significantly associated with PrCa risk were identified in ERCC3 (rs145201970, p=2.57×10 −4 ) and BRIP1 (rs4988345, p=0.025) in the combined datasets. A PARP2 (rs200603922, p=0.028) variant in the Australian dataset and a MUTYH (rs36053993, p=0.031) variant in the North American dataset were also associated with PrCa risk. No evidence for a younger age or higher-grade disease at diagnosis was evident in variant carriers. Conclusions Here, we provide new evidence for four novel germline DDR PrCa risk variants. Defining the full spectrum of PrCa associated DDR genes is important for effective clinical screening and disease management.