Study Finds Incidence of Mutations in DNA-Repair Genes Significantly Higher in Men With Metastatic Prostate Cancer
The incidence of mutations in DNA-repair genes was significantly higher among men with metastatic prostate cancer than among men with localized disease (11.8% vs 4.6%), according to a study by Pritchard et al reported in The New England Journal of Medicine. In addition, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer did not differ significantly according to age at diagnosis or family history of prostate cancer.
Study Methodology
The researchers analyzed data from 692 men with documented metastatic prostate cancer across multiple institutions in the United States and the United Kingdom. All the patients were unselected on the basis of family history of cancer, age, or any knowledge of genetic background. Then germline DNA was isolated, and multiple sequencing assays were used to assess mutations in 20 DNA-repair genes associated with autosomal-dominant cancer-predisposition syndromes.
Study Results
A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious in 82 men (11.8%) were found; mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 men [1.6%]), CHEK2 (10 men [1.9% of 534 men with data]), BRCA1 (6 men [0.9%]), RAD51D (3 men [0.4%]), and PALB2 (3 men [0.4%]). The frequency of mutation did not differ according to whether a family history of prostate cancer was present or age at diagnosis.
Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P < .001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which included 53,105 persons without a known cancer diagnosis (P < .001).
Clinical and Research Implications
“These findings are of interest for two reasons,” said Kenneth Offit, MD, MPH, Chief of Clinical Genetics Service; Head of the Memorial Sloan Kettering Cancer Center’s Robert and Kate Niehaus Center for Inherited Cancer Genomics; and a co–senior author of this study, in a statement. “First, these findings potentially change clinical practice because we now show that testing for these DNA repair genes should be offered to all men with advanced prostate cancer. The second important finding is that we see clusters of cancers other than prostate, breast, ovarian, and pancreatic in these families that were not expected and that will stimulate further research.”
Peter Nelson, MD, at the Division of Human Biology at the Fred Hutchinson Cancer Research Center, is the corresponding author of this study.
Funding for this study was provided by a Stand Up To Cancer-Prostate Cancer Foundation International Prostate Cancer Dream Team Translational Cancer Research Grant, the National Institutes of Health, the Department of Defense, and the Prostate Cancer Foundation.
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