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Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer
  1. Steven N Hart1,2,
  2. Marissa S Ellingson1,
  3. Kim Schahl1,
  4. Peter T Vedell2,
  5. Rachel E Carlson2,
  6. Jason P Sinnwell2,
  7. Poulami Barman2,
  8. Hugues Sicotte2,
  9. Jeanette E Eckel-Passow2,
  10. Liguo Wang1,2,
  11. Krishna R Kalari1,2,
  12. Rui Qin2,
  13. Teresa M Kruisselbrink1,
  14. Rafael E Jimenez3,
  15. Alan H Bryce4,
  16. Winston Tan5,
  17. Richard Weinshilboum1,6,
  18. Liewei Wang1,6,
  19. Manish Kohli7
  1. 1Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Division of Hematology/Oncology, Mayo Clinic, Mayo Clinic Cancer Center, Scottsdale, Arizona, USA
  5. 5Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA
  6. 6Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
  7. 7Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, USA
  1. Correspondence to Dr Manish Kohli; kohli.manish{at}


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.

  • Prostate cancer
  • Genetic testing
  • Cancer Risk
  • Germline
  • BRCA2

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