Inherited Mutations Common Among Men With Metastatic Prostate Cancer

By: Germline mutations in genes that maintain DNA integrity appear in a significant proportion of men with metastatic prostate cancer (PCa), according to a new study published in the New England Journal of Medicine.  

Among men with metastatic PCa, 11.8% had inherited mutations that are presumed to be harmful compared with just 4.6% of men with localized PCa and 2.7% of the general population.

"The result is surprising and important for men with prostate cancer as this information may prioritize certain therapies,” Peter Nelson, MD, of Fred Hutchinson Cancer Research Center in Seattle, and senior author of the study stated in a press release. “These findings present a compelling argument for updating prostate cancer screening guidelines to include germline DNA testing as a part of standard care for men with  metastatic prostate cancer." 

For the study, Dr Nelson and colleagues determined the incidence of DNA-repair gene mutations in 692 men with metastatic PCa from 7 case series across multiple institutions in the United States and United Kingdom. They then compared it to the frequencies among patients with localized PCa using public data on 499 patients from the Cancer Genome Atlas prostate cancer study and a general population of 53,105 without known cancer from the Exome Aggregation Consortium. Men with metastatic PCa were recruited without regard to family history, age, or genetic background.

The investigators isolated germline DNA and used multiple sequencing assays to assess mutations in 20 DNA-repair genes linked with syndromes that predispose to autosomal dominant cancer. A total of 84 pathogenic mutations were found in 16 genes, such as BRCA2 (prevalent in 44% of men with these mutations), ATM (13%), CHEK2 (12%), and BRCA1 (7%). Notably, the chances of having these mutations did not differ by age at diagnosis or family history of PCa.

The study has important clinical implications, according to Dr Nelson and colleagues. Genetic testing for these mutations could identify patients who may benefit from precision treatments. For example, other research indicates these patients may respond to poly-ADP ribose polymerase inhibitors, which target vulnerabilities in the DNA repair process within cancer cells, and platinum-based chemotherapy. “It is also important for family members as they may have inherited a gene that predisposes them to developing one of several types of cancer [such as breast, ovarian, pancreatic] and heightened awareness could enhance early detection and treatment,” Dr Nelson stated.

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