To determine the frequency of pathogenic inherited mutations in 157 select genes from patients with metastatic castrate-resistant prostate cancer (mCRPC).
Setting Multisite US-based cohort.
Seventy-one adult male patients with histological confirmation of prostate cancer, and had progressive disease while on androgen deprivation therapy.
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.
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.
Citation: Steven N Hart, Marissa S Ellingson, Kim Schahl, Peter T Vedell, Rachel E Carlson, Jason P Sinnwell Determining The Frequency Of Pathogenic Germline Variants From Exome Sequencing In Patients With Castrate-resistant Prostate Cancer BMJ Open 2016;6:e010332 doi:10.1136/bmjopen-2015-010332
Received: 21 October 2015 Revised: 23 December 2015 Accepted: 9 February 2016 Published: 15 April 2016
Copyright: This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
MSE, TMK and KS classified and reviewed variants. SNH, PTV, HS, LW and KRK were responsible for the DNA sequencing and informatics. REC, JPS, PB, JEE-P and RQ coordinated the statistical analysis. WT, MK and AHB led the patient recruitment effort. The entire study was supervised and directed by RW, LW and MK. SNH, MSE and MK wrote the paper.
Mayo Clinic Cancer Center (P30CA 15083-41). Joseph and Gail Gassner. Mayo Clinic Schulze Cancer for Novel Therapeutics in Cancer Research. Pharmacogenomics Research Network. A. T. Suharya and Ghan D. H. Mayo Clinic Center for Individualized Medicine.
Competing interests None declared.