Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer

Objectives: To determine the frequency of pathogenic inherited mutations in 157 select genes from patients with metastatic castrate-resistant prostate cancer (mCRPC). Design: Observational. Setting: Multisite US-based cohort. Participants: Seventy-one adult male patients with histological confirmation of prostate cancer, and had progressive disease while on androgen deprivation therapy. Results: Twelve patients (17.4%) showed evidence of carrying pathogenic or likely pathogenic germ line variants in the ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR and WRN genes. All but one patient opted in to receive clinically actionable results at the time of study initiation. We also found that pathogenic BRCA2 variants appear to be enriched in mCRPC compared to familial prostate cancers. Conclusions: Pathogenic variants in cancer susceptibility genes are frequently observed in patients with mCRPC. A substantial proportion of patients with mCRPC or their family members would derive clinical utility from mutation screening. Trial registration number: NCT01953640; Results.