Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

<strong>BACKGROUND:</strong> Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in <i>BRCA2</i> and <i>BRCA1</i> give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate <i>RAD51B</i> and <i>RAD23B</i>.<p></p> <p><strong>METHODS:</strong> 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.</p> <p><strong>RESULTS:</strong> Single SNP analyses identified only the previously reported association with <i>RAD51B</i>. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for <i>MSH5</i>. 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.</p> <p><strong>CONCLUSIONS:</strong> <i>MSH5</i> is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. <i>MSH5</i> has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.</p>