Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers

Hyuna Sung, Howard H Yang, Han Zhang, Qi Yang, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao (+13 others)
2015 International Journal of Epidemiology  
Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. Methods: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with
more » ... e ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses. Results: Suggestive pathway-based associations were observed for the overall epigenetic (P-value PATH ¼ 0.034) and chromatin remodelling (P-value PATH ¼ 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value GENE < 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho ¼ 0.37; P ¼ 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues. Conclusions: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer. • We investigated the relation of genetic variation in genes in the epigenetic pathway and subpathways to risk of upper gastrointestinal (UGI) cancers. • We found suggestive evidence for associations between gastric cardia cancer and the epigenetic pathway as well as the chromatin remodelling subpathway. • The top-ranked epigenetic pathway genes associated with UGI cancer were predominantly from the chromatin remodelling subpathway. • Expression quantitative trait loci (eQTL) analyses found several SNPs whose variants may regulate mRNA levels of important chromatin remodelling and microRNA biosynthesis genes associated with UGI cancer risk. • This analysis, the first comprehensive assessment relating epigenetic pathway gene variation to risk of UGI cancer, provides limited evidence suggesting a role for epigenetic pathway in UGI cancer susceptibility.
doi:10.1093/ije/dyv050 pmid:25921222 pmcid:PMC4598798 fatcat:34f73rapvje3nbsv736vbu77ki