DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human
carcinogenesis. To detect critical methylation events associated with
gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal
metaplasia (IM), and gastric
tumor (GT) cells that were microscopically dissected from an intestinal-type early
gastric cancer (EGC) using methylated
DNA binding domain sequencing (MBD-seq) and reduced representation
bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (
DMPs) that could be directly associated with gene expression. We detected 2,761 and 677
DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035
DMPs. Then, 514 (17%) of all
DMPs were detected in the IM genome, which is a precancer of GC, supporting that some
DMPs might represent an early event in gastric
carcinogenesis. A pathway analysis of all
DMPs demonstrated that 59 G
protein-coupled receptor (GPCR) genes linked to the hypermethylated
DMPs were significantly enriched in a neuroactive
ligand-receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI
hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of
gastrin or gastric acid were selected and validated as potential
biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI)
hormone receptors by promoter methylation may lead to gastric
carcinogenesis because
gastrin and gastric acid have been known to play a role in cell differentiation and
carcinogenesis in the GI tract.