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, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P. Lee, Stephen J. Chanock, Sanford M. Dawsey, Neal D. FreedmanChristian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor, Paula L. Hyland

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 Chinese 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-valuePATH=0.034) and chromatin remodelling (P-valuePATH=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-valueGENE<0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho=0.37; P=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.

Original languageEnglish (US)
Pages (from-to)1341-1352
Number of pages12
JournalInternational journal of epidemiology
Volume44
Issue number4
DOIs
StatePublished - Aug 2015

Keywords

  • Chromatin remodelling
  • DNA methylation
  • Epigenetics
  • Gastric cancer
  • Gastric cardia
  • Gastric non-cardia
  • Gene-based
  • MicroRNA
  • Oesophageal squamous cell carcinoma
  • Pathway-based
  • SNP

ASJC Scopus subject areas

  • Epidemiology

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