Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype

Hypermethylation of the hMLH1 mismatch repair gene promoter has been reveal ed to lead to microsatellite instability (MSI). Previously, we demonstrated a high prevalence of MSI in differentiated-type gastric tumors showing dis tinct features of gastric foveolar epithelium (foveolar type). To clarify t he significance of hMLH1 promoter hypermethylation in the development of th is tumor type, we studied promoter methylation status and expression of hML H1 in foveolar-type tumors and their surrounding non-neoplastic mucosae, as well as in tumors with other cellular phenotypes. The results were compare d to MSI status. After phenotypical analyses using mucin histochemistry and immunohistochemistry, 41 differentiated-type tumors with distinct cellular phenotypes were classified into three categories: foveolar type, intestina l type (tumors with the distinct cellular phenotype of the intestine), and combined type (tumors with both foveolar and intestinal phenotypes), Methyl ation-specific polymerase chain reaction (MSP) was performed to determine t he methylation status of hMLH1 promoter. hMLH1 protein expression was immun ohistochemically examined. MSI was detected in 57% of the foveolar type, 8% of the intestinal type, and 67% of the combined-type tumors. Hypermethylat ion of hMLH1 promoter was found in 74% of the foveolar type, 33% of the int estinal type, and 83% of the combined-type tumors. Of 18 MSI-positive tumor s, all but one were hypermethylated, Methylation status of hMLH1 promoter c orrelated well with protein expression in foveolar-type tumors. Moreover, h ypermethylation was also detected frequently (71%) in the non-neoplastic su rrounding mucosa of the hypermethylated tumors. Hypermethylation of hMLH1 p romoter is an initial, vital event in the development of foveolar-type tumo rs of the stomach.