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NEW YORK (Reuters Health) – Nearly two dozen unique DNA-repair genes are associated with prostate-cancer predisposition or the risk of aggressive disease, researchers report.

Previous studies have implicated germline mutations in several DNA-repair genes as contributors to prostate-cancer predisposition.

Dr. Zsofia Kote-Jarai from The Institute of Cancer Research, in London, and colleagues screened 167 genes from DNA-damage-response and -repair pathways among 1,281 men with prostate cancer diagnosed at or before age 60 years and in 1,160 controls matched for genetic ancestry.

Variants in NBN were significantly associated with prostate-cancer predisposition, and variants in XPC were significantly tied to aggressive disease. HOXB13 and POLL were also marginally associated with aggressive disease, the researchers report in European Urology, online February 15.

In a separate analysis, a set of 20 genes was significantly enriched among prostate-cancer cases (8.5%) versus controls (2.8%), and only five of these genes overlap with a previously identified gene set associated with prostate cancer.

The analysis also identified four genes associated with aggressive disease, but only one (ERCC2) was unique to patients with aggressive disease (the other three overlapped with the prostate-cancer-predisposition set).

“Prostate cancer patients who are carriers of mutations in these genes could potentially benefit from personalized treatment pathways,” the researchers conclude. “We believe that these genes warrant evaluation by the wider scientific and clinical communities in larger prospective studies or meta-analyses.”

“There is also a need to formally test the ability of these genes to predict survival in an independent cohort within aggressiveness strata,” they add.

Dr. Emmanuel S. Antonarakis from Johns Hopkins University School of Medicine, in Baltimore, Maryland, who recently reviewed treatment strategies for DNA-repair-deficient prostate cancer, told Reuters Health by email, “As more and more targeted systemic therapies are being discovered for use in men with germline or somatic DNA-repair-gene mutations, these findings may expand the use of drugs such as PD-1 inhibitors or PARP inhibitors in men with germline mismatch-repair and homologous-recombination repair mutations, respectively.”

“Germline testing for inherited forms of prostate cancer, especially in patients diagnosed before age 60, may require an expanded panel of genes that goes beyond BRCA1/2 and ATM,” said Dr. Antonarakis, who was not involved in the new work. “These results require confirmation before more expansive genetic testing protocols are implemented.”

Dr. Kote-Jarai did not respond to a request for comments.


Eur Urol 2019.

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