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

BMJ Open. 2016 Apr 15;6(4):e010332. doi: 10.1136/bmjopen-2015-010332.


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 germline 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 germline 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.

Keywords: BRCA2; Cancer Risk; Genetic testing; Germline; Prostate cancer.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • BRCA2 Protein / genetics
  • Exome*
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Prostatic Neoplasms, Castration-Resistant / genetics*
  • Prostatic Neoplasms, Castration-Resistant / pathology


  • BRCA2 Protein
  • BRCA2 protein, human
  • Neoplasm Proteins

Associated data