The prevalence of inherited mutations in DNA repair genes such as BRCA2 in men with metastatic prostate cancer may be as high as 12%, investigators in a multicenter study report.
The prevalence of presumably harmful mutations in men with metastatic disease was more than twice that of men with localized prostate cancer, and men with metastatic prostate cancer had a 3- to 19-fold higher risk for having mutations in individual DNA repair genes, compared with men without prostate cancer in a population-wide genetic sample, reported Colin C. Pritchard, MD, PhD, of the University of Washington in Seattle and colleagues.
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“Because the high frequency of DNA repair gene mutations is not exclusive to an early-onset phenotype and is associated with clinically and histologically aggressive disease, with compelling evidence for therapeutic relevance, it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA repair genes,” the investigators suggest (N Engl J Med. 2016 July. doi: 10.1056/NEJMoa1603144).
The findings point to possible therapeutic interventions for men with advanced prostate cancer with identified germline mutations in DNA repair genes, such as poly (ADP-ribose) polymerase (PARP) inhibitors or platinum compound–based chemotherapy,
To date, the only genetic factors known to be associated with aggressive prostate cancer and prostate cancer–specific mortality are mutations in DNA repair genes such as BRCA1 and BRCA2, CHEK2, and PALB2. The frequency of mutations in these genes among men with localized prostate cancer in general is relatively low, accounting for just a few percentage points of familial prostate cancer cases in a sample unselected for family predisposition, the authors noted.
To determine the frequency of mutations in advanced disease, the investigators reviewed genetic data on 692 men with metastatic prostate cancer who were enrolled in one of seven cases series and were unselected for family history of cancer or age at diagnosis.
They used multiplex genetic sequencing assays to look for mutation in 20 DNA repair genes that are associated with autosomal dominant cancer predisposition syndromes.
They found 84 presumably harmful mutations in 82 men, for an overall prevalence of 11.8%. In contrast, the frequency of germline DNA repair mutations among 499 men in the Cancer Genome Atlas prostate cancer study, including men with high-risk disease, was 4.6%, the authors noted.
The mutations occurred in 16 different genes, including, in order of prevalence, BRCA2, ATM, CHEL2, BRCA1, RAD51D and PALB2. There were no significant differences in mutation frequencies by either family history of prostate cancer or age at diagnosis.
The authors also estimated the prevalence of DNA repair gene mutations among the general population by looking at a sample of 53,105 persons without a known diagnosis of cancer who were included in the Exome Aggregation Consortium. Men with metastatic prostate cancer had a fivefold risk for having any deleterious DNA repair mutation, compared with the general population (P less than .001).
The relative risk of mutations in individual genes for men with metastatic disease, compared with men in the control sample, ranged from 3.1 for CHEK2 (P = .002) to 18.6 for BRCA2 (P less than .001).
The study was supported by a Stand Up To Cancer–Prostate Cancer Foundation (SU2C-PCF) International Prostate Cancer Dream Team Translational Cancer Research Grant and awards from the National Institutes of Health, Department of Defense, and prostate cancer foundation. Several authors reported receiving research fees, grants, honoraria, and/or travel expenses from various pharmaceutical companies.