Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel.
case_control · Level III
Where this comes from
- Record sourced from PubMed, PMID 30777372.
- Also identified by DOI 10.1016/j.eururo.2019.01.050 and PMC identifier 6695475.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls. Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and 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. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (p<sub>SKAT-O</sub>=2.4×10<sup>-4</sup>) for overall risk and XPC (p<sub>SKAT-O</sub>=1.6×10<sup>-4</sup>) for aggressive disease, both at candidate-level significance (p<3.1×10<sup>-4</sup> and p<3.4×10<sup>-4</sup>, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, p<sub>ADA</sub>=4.1×10<sup>-3</sup>) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, p<sub>ADA</sub>=5.6×10<sup>-3</sup>), three 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 predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.
Medical subject headings
- DNA Repair
- DNA, Neoplasm
- Genetic Predisposition to Disease
- Genetic Testing
- Germ-Line Mutation
- Prostatic Neoplasms