A Cross-Cancer Genetic Association Analysis of the DNA repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast and Colorectal Cancer

BACKGROUND: Though DNA damage is an established mediator of carcinogenesis, GWAS have identified few significant loci, associated with cancer predisposition, within DNA repair gene regions. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility. METHODS: We conducted a cross-cancer analysis of 60,297 SNPs, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software package. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling. RESULTS: We identified three susceptibility DNA repair genes, RAD51B (p <5.09 x 10-6), MSH5 (p <5.09 x 10-6) and BRCA2 (p = 5.70 x 10-6). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways. CONCLUSIONS: Only three individual susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways. IMPACT: These data suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.