Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation

Aberrant hypermethylation of promoter CpG islands is an important mechanism for the inactivation of tumor suppressor genes. CpG island hypermethylation occurs in relation to tumorigenesis or aging. Gastric cancer is one of the tumors with a high level of aberrant CpG island methylation. However, the data on the methylation status of normal gastric mucosa has been very limited. The present study attempted to compare the methylation status of nonneoplastic gastric mucosa, using clinicopathological parameters, including age, gender, Helicobacter pylori (H. pylori), acute and chronic inflammation, and intestinal metaplasia. Two hundred sixty-eight nonneoplastic gastric mucosa samples were studied for the methylation status of 11 genes (COX-2, DAP-kinase, E-cadherin, GSTP1, MGMT, hMLH1, p14, p16, THBS1, TIMP3, and RASSF1A), using methylation-specific PCR. CpG island hypermethylation was found in 53.7, 41, 37.7, 23.1, 18.7, 10.9, 10, 4.1, 3.4, 1.7, 0.4% for DAP-kinase, E-cadherin, THBS1, TIMP3, p14, MGMT, p16, COX-2, GSTP1, hMLH1 and RASSF1A, respectively. Five genes (DAP-kinase, E-cadherin, p14, THBS1, and TIMP-3) showed a general progressive increase in the methylation frequency as a function of aging, whereas the other genes (COX-2, GSTP1, MGMT, hMLH1, p16, and RASSF1A) were rarely methylated. Male patients showed higher numbers of methylated genes than females (3.2 vs. 2.1, respectively, P = 0.002). Gastritis samples with marked intestinal metaplasia, showed higher numbers of genes methylated than those without (3.7 vs. 2.6, respectively, P = 0.021). Gastritis samples with marked infiltration of mononuclear cells displayed higher numbers of genes methylated than those with mild or moderate infiltration of mononuclear cells (3.4 vs. 2.5 or 2.5, respectively, P < 0.05). Our results demonstrated that many genes are methylated in the stomach as a function of age, and suggested that male gender, intestinal metaplasia, and chronic inflammation are closely associated with increased methylation in nonneoplastic gastric mucosa samples.