Results from a recent study evaluating the rate of inherited DNA repair gene mutations in patients with prostate cancer yielded a panel of 23 genes that could improve risk prediction or treatment pathways in future clinical practice (Eur Urol. 2019 Feb 15. Epub ahead of print).

“Rare germline mutations in DNA repair genes are associated with prostate cancer…predisposition and prognosis,” explained Daniel A. Leongamornlert, PhD, Oncogenetics, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom, and colleagues.

Seeking to comprehensively assess how individual genes contribute to overall prostate cancer risk and the likelihood of aggressive disease, Dr Leongamornlert and his team quantified and compared the frequency of germline DNA repair gene mutations between patients with prostate cancer (n = 1281) and disease-free controls (n = 1160).

Using a cohort based in the United Kingdom, they sequenced a total of 167 DNA repair genes and 8 prostate cancer candidate genes, and performed separate analyses of gene-level SKAT-O and gene-set adaptive combination P values (ADA) for patients with cancer versus controls, and for aggressive (Gleason score ≥8; n = 201) versus nonaggressive (Gleason score ≤7; n = 1048) cases.

“We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes,” Dr Leongamornlert and colleagues reported.

Overall, there were more carriers of PTV among the patients with prostate cancer than among the healthy controls (15% vs 12%, respectively; odds ratio [OR], 1.29; 95% confidence interval [CI], 1.01-1.64; P = .036).

At candidate-level significance, gene-level analyses identified NBN (PSKAT-O = 2.4 × 10-4) for overall risk and XPC (PSKAT-O = 1.6 × 10-4) for aggressive disease.

In addition, the gene-set analysis identified a subset of 20 genes linked with an increased risk for prostate cancer (OR, 3.2; 95% CI 2.1-4.8; PADA = 4.1 × 10−3) and 4 genes that were associated with an increased risk for aggressive disease (OR, 11.2; 95% CI, 4.6-27.7; PADA = 5.6 × 10-3), 3 of which overlap the predisposition gene set.

“The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa [prostate cancer] predisposition or risk of aggressive disease,” Dr Leongamornlert and colleagues said.

“These findings will help facilitate the development of a PCa[prostate cancer]-specific sequencing panel with both predictive and prognostic potential,” they concluded.—Hina Khaliq