Abstract
Background:Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B.Methods:Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes.Results:Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant.Conclusions:MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.
Highlights
Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer
MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers
DNA repair gene variation and prostate cancer risk prostate-specific antigen test for clinically relevant forms of the disease could potentially lead to considerable over-diagnosis and overtreatment of patients for relatively modest reductions in mortality (Ilic et al, 2013)
Summary
Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. Samples for the iCOGS study were drawn from 25 studies participating in the PRACTICAL Consortium. The majority of studies were population-based or hospital-based case–control studies, or nested case–control studies; some studies selected samples by age or oversampled for cases with a family history of prostate cancer. Further information regarding the samples from the PRACTICAL Consortium included on the iCOGS array may be found within the original publication (Eeles et al, 2013). Analyses for DNA-repair gene variants were restricted to samples of European ancestry. Genotype data for 21 780 PrCa cases and 21 727 matched controls were available after quality control
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