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Updated: Jul 4, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Integrative analysis of gastric tissue transcriptomes and gastric cancer GWAS implicates candidate susceptibility
Beiping Hu1, Min Zhang2, Yuhui Yu3
1Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; State Key Laboratory Cultivation Base of Biomarkers for Cancer Precision Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine and China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, China; Department of Chronic Non-Communicable Disease Control, Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center of Nanjing Medical University, Wuxi, China.
Abstract:
Genome-wide association studies (GWASs) have identified at least 17 genetic variants associated with gastric cancer risk. However, the underlying genetic regulatory mechanisms remain poorly understood. We systematically performed genome-wide analyses of expression quantitative trait loci (eQTLs), splicing QTLs (sQTLs), and alternative polyadenylation QTLs (apaQTLs) using gastric biopsy tissues from 262 Chinese individuals, and we integrated these data with GWAS results from 10,254 gastric cancer cases and 10,914 controls. We identified 4,636 eGenes, 1,422 sGenes, and 511 apaGenes, with 55.3% of sGenes and 49.5% of apaGenes being distinct from eGenes. Notably, over half of the variants associated with shared genes were unique to a specific QTL type, with these variants characterized by a wide physical separation (median distance = 25.01 kb) and weak linkage disequilibrium (median r2 = 0.42). Gastric cancer risk variants showed significant enrichment across all three QTL categories. Integrative transcriptome-wide association studies (TWASs) across expression, splicing, and alternative polyadenylation identified 34 genes at false discovery rate (FDR) <0.05; PSCA was implicated across all three regulatory layers. The candidates DIP2B and RMC1 were experimentally validated to promote gastric tumorigenesis both in vitro and in vivo. Functional analyses revealed that the rs11264361-T allele reduced FDPS exon 9 skipping, leading to increased expression of the full-length transcript, while the apaVariant rs7445 regulated UBE2L3 polyadenylation via ATXN2 binding, contributing to gastric cancer risk. Collectively, these results provide a comprehensive QTL resource in gastric tissues and demonstrate distinct regulatory mechanisms of eQTLs, sQTLs, and apaQTLs in gastric cancer development.
