High Prostate Cancer Risk Linked to Inherited Mutations in DNA-repair Genes

High Prostate Cancer Risk Linked to Inherited Mutations in DNA-repair Genes

Mutations in DNA-repair genes, including the breast cancer genes BRCA1 and BRCA2, are involved in an inherited high risk of prostate cancer and, potentially, the risk of an aggressive cancer, according to researchers at Fred Hutchinson Cancer Research Center and the University of Washington.

The study, “Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer,” published in The New England Journal of Medicine, found the mutations in about 12 percent of men with the cancer — and found that men with metastatic prostate cancer were five times more likely than most people to have these DNA-repair gene mutations. Results suggest that screening for such mutations could help tailor their treatment and encourage family members to consider their own cancer risk.

“I think these data really suggest that we need to engage men in discussions about genetics, where it has not been central before,” Dr. Heather Cheng, a Fred Hutch and University of Washington prostate cancer researcher, said in a press release.

Because BRCA1 and BRCA2 mutations have long been associated only with breast and ovarian cancers, it was thought that the mutations only affected women.

The team analyzed 20 DNA-repair genes in metastatic prostate tumors and healthy tissues of 692 men. They found that 16 of the genes were mutated in both malignant and healthy cells in 12 percent of the metastatic cancer patients — much higher than researchers ever suspected, said first author Dr. Colin Pritchard.

“The implications are big in terms of intercepting and preventing a cancer because [carriers of these mutations] are at high risk,” said Dr. Pete Nelson, a Fred Hutch prostate cancer researcher and senior author on the study.

The findings are also important because men with advanced prostate cancer who have the mutations in DNA-repair genes could be treated with PARP inhibitors or platinum chemotherapy, which is commonly used in breast cancer patients. Although not yet approved for prostate cancer treatment, the treatments are on fast-track review by the U.S. Food and Drug Administration.

“For men with metastatic disease who are found to have these mutations, there are very clear treatment implications that would not otherwise be considered for prostate cancer. It would essentially expand [the patients’] toolbox of treatments,” Cheng said.

The researchers hope the findings will land the screening in National Comprehensive Cancer Network guidelines — with future coverage by insurance companies.

“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 authors concluded.

Future work by investigators will focus on determining which mutations predispose patients to the most aggressive type of prostate cancer.

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