p16(INK4a) Promoter hypermethylation of non-tumorous tissue adjacent to gastric cancer is correlated with glandular atrophy and chronic inflammation.

The p16(INK4a) tumor suppressor gene can be inactivated by promoter region hypermethylation in many tumor types including gastric cancers. However, p16(INK4a) promoter hypermethylation in the surrounding non-tumorous tissues of gastric cancers has not been studied in detail. We therefore examined 46 gastric cancers, corresponding adjacent non-tumorous tissue samples and 8 gastric tissue samples of chronic gastritis by performing methylation-specific polymerase chain reaction, and we analyzed p16(INK4a) protein expression using immunohistochemistry and Western blot. p16(INK4a) promoter hypermethylation was observed in 43% of gastric cancers and 59% of adjacent non-tumorous tissues; however, none of the samples retrieved from the chronic gastritis patients displayed p16(INK4a) promoter hypermethylation. Gastric cancers showed an inverse correlation between vascular invasion and p16(INK4a) promoter hypermethylation, and adjacent non-tumorous tissues displayed a close association among the grade of chronic inflammation, presence of glandular atrophy and p16(INK4a) promoter hypermethylation. p16(INK4a) expression was markedly decreased in samples with p16(INK4a) promoter hypermethylation when compared with samples without p16(INK4a) promoter hypermethylation. These results suggest that p16(INK4a) promoter hypermethylation is an early and frequent event in gastric carcinogenesis and may serve as a new prognostic biomarker for the risk of gastric cancers.