Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False-discovery-rate corrected p-values (q-values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, ER-negative breast, overall prostate, overall and serous ovarian cancer; the most significant variant was rs4808076 (odds ratio (OR)=1.14, 95% confidence interval (CI)=1.10-1.19, q=6.87*10-5). DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, overall and aggressive prostate cancer risk (OR=0.93, 95% CI=0.91-0.96, q=0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, estrogen receptor (ER)-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g. rs9388766: OR=1.06, 95% CI=1.03-1.08, q= 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian and endometrioid ovarian cancer risk, rs62331150 showing bidirectional effects. Analyses of sub-pathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusion: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.
- Received September 9, 2016.
- Revision received December 16, 2016.
- Accepted December 19, 2016.
- Copyright ©2017, American Association for Cancer Research.