Methylation and expression of non-clustered protocadherins encoding genes and risk of precancerous gastric lesions in a high-risk population

Abstract

Non-clustered protocadherins (PCDHs) family is a group of cell-cell adhesion molecules. We have found differentially methylated genes in the non-clustered PCDHs family associated with Helicobacter pylori (H. pylori) infection in prior genome-wide methylation analysis. To further investigate the methylation and expression of non-clustered PCDHs encoding genes in H. pylori-related gastric carcinogenesis process, four candidate genes including PCDH7, PCDH10, PCDH17 and PCDH20 were selected, which were reported to be tumor suppressors for digestive cancers. A total of 747 participants with a spectrum of gastric lesions were enrolled from a high-risk population of gastric cancer. Promoter methylation levels of four genes were significantly higher in H. pylori positive subjects than the negative group (all P<0.001). Elevated methylation levels of PCDH10 and PCDH17 were observed with the increasing severity of gastric lesions (both Ptrend<0.001). In the protein expression analysis, PCDH17 expression was inversely associated with gastric lesions; the OR (95% CI) was 0.49 (0.26-0.95) for chronic atrophic gastritis (CAG), 0.31 (0.15-0.63) for intestinal metaplasia, and 0.38 (0.19-0.75) for indefinite dysplasia and dysplasia, compared with superficial gastritis (SG). In addition, PCDH10 expression was significantly lower in CAG (OR=0.40, 95% CI=0.24-0.68). The inverse association between methylation and protein expression of PCDH10 and PCDH17 was further supported when we explored the methylation and mRNA expression in The Cancer Genome Atlas database (all P<0.001). Our study found elevated promoter methylation and decreased expression of PCDH10 and PCDH17 in advanced gastric lesions, suggesting that elevated PCDH10 and PCDH17 methylation may be an early event in gastric carcinogenesis.