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

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-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 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 = 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.

Keywords: DNA methylation; Epigenetics; SNP; chromatin remodelling; gastric cancer; gastric cardia; gastric non-cardia; gene-based; microRNA; oesophageal squamous cell carcinoma; pathway-based.

Figure 1.

Expression quantitative trait loci (eQTL) analysis of ASH1L mRNA expression in normal gastric tissues, and genomic locations for ASH1L and SNPs. A: eQTL analyses were conducted using dominant model for rs12724079 in 90 gastric tissues, rs8179271 in 34 cardia tissues and rs12724079 in 56 non-cardia tissues. ASH1L mRNA levels were assessed using the Affymetrix_U133A probe 218 554_s_at. The major/minor allele for each SNP in our population is shown. B: Genome Browser [http://genome.ucsc.edu/] image of ASH1L gene region on human assembly hg19 based on NIH Epigenomics Roadmap data [http://www.genboree.org/epigenomeatlas/] and ENCODE data [http://genome.ucsc.edu/ENCODE/]. The position of the Affymetrix_U133A probe 218 554_s_at, which detects variant mRNAs 1, 2 and 3 of ASH1L and CpG islands in this region are shown. Regulatory domains [chromatin state segmentation using a hidden Markov Model (ChromHMM)] and core histone marks for normal gastric tissue (Gastric), stomach mucosa (SM) and stomach smooth muscle (SSM) tissue are shown: Red, active transcriptional start site (TSS); Dark Green, transcription elongation/transition; Orange, active-to-weak enhancer. H3K4Me3 and H3K27Ac activation marks in this region and mRNA levels from a large number of ENCODE cells lines is also shown. SNPs rs12724079 and rs8179271 are highlighted by a light blue-coloured box. For clarity, not all SNPs contained in this region (dbSNP) are shown. ASH1L-AS1 and other non-coding RNA genes within ASH1L are indicated and text is coloured grey.