Background: Populations in north central China are at high risk for esophageal 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 (AdaJoint) to analyze 191 epigenetic genes involved in DNA methylation, chromatin remodeling, and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined the regulatory function of risk SNPs using in silico analyses and expression quantitative trait loci (eQTL) analysis in normal esophageal and gastric tissues. Results: Significant pathway-based associations were observed for the overall epigenetics (P = 3.4E-02) and chromatin remodeling (P = 3.9E-02) pathways with GCA risk, but not GC, GNCA or ESCC. SETD1B, CBX4, KAT5, ZGPAT, BTD, EED, SMARCD1, POLE3, AGO2, RING1 and MBD3L1 were associated with ESCC risk, and SUV42OH1, ASH1L, KAT5, JARID2, PRMT1, MBD3L1, SRRT, KDM5A, DROSHA and KAT6A were associated with GC risk overall (nominal P < 0.05). We identified EED rs10898459 (rho = -0.22, P = 2.9E-02) as a potential esophageal eQTL; DICER1 rs7157322 (rho = -0.42, P = 1.4E-02) and PPP1CA rs1790733 (rho = -0.41, P = 2.1E-03) as potential gastric eQTLs; and ASH1L rs12724079 and rs8179271 as potential gastric subtype eQTLs. Significance: As one of the first attempts to investigate epigenetic gene and pathway-level associations, our results suggest that chromatin remodeling and epigenetic pathways warrant further evaluation in relation to GC risk in other populations.

Citation Format: 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, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P. Lee, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor, Paula L. Hyland. Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4622. doi:10.1158/1538-7445.AM2015-4622