Microsatellite instability of papillary subtype of human gastric adenocarcinoma and hMLH1 promoter hypermethylation in the surrounding mucosa

Gastric cancer has striking heterogeneity in histological pattern, cellular phenotype, genotype, biomarkers, and biological behavior. We focused on th e specific morphological papillary phenotype of gastric adenocarcinoma and attempted to identity its distinct molecular characteristics. In our compar ative study, early stage papillary (papillary-dominant) gastric cancer show ed a significantly higher and more widespread high-frequency microsatellite instability (MSI-H) than other morphological types. Analysis of mutations in a panel of five putative microsatellite instability (MSI)-associated gen es in the MSI-H cases revealed that papillary or papillary-dominant cancer displays a unique profile of mutations compared to profiles previously repo rted in gastric cancer. Immunohistochemical staining and methylation analys is revealed that silencing of hMLH1 by methylation in its promoter region w as responsible for the failure of mismatch repair in papillary-type gastric cancer, whereas aberrant promoter methylation of hMLH1 was not found in an y cases without the unique mutator phenotype. Promoter hypermethylation of the hMLH1 genes was found to a lesser degree in the adjacent non-tumor muco sa in four of the 10 cases with tumor having the mutator phenotype. Microsa tellite instability itself could not be detected in the adjacent non-tumor mucosa. Inactivation of hMLH1 expression by promoter hypermethylation may b e an early event in carcinogenesis of this type of gastric cancer, precedin g the development of the clear MSI phenotype of papillary carcinoma.