hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability

Mutation of DNA mismatch repair genes has rarely been documented in sporadi c gastric carcinoma with microsatellite instability (MSI), In sporadic colo rectal carcinoma, hMLH1 promoter methylation associated with protein loss i s found in the majority of high-frequency MSI cases. We investigated a seri es of 35 sporadic gastric carcinomas stratified into high-frequency MSI (MS I-H), low-frequency MSI (MSI-L) and microsatellite stable (MSS) groups and found that hypermethylation of the CPG island in the hMLH1 promoter region was present in 100% of MSI-H sporadic gastric carcinomas. In 90% of cases, there was an associated complete loss of hMLH1 protein, as detected by immu nohistochemistry, and a markedly lowered hMLH1 mRNA level. This loss of hML H1 protein occurred in the MSI-H invasive tumor but not in the adjacent car cinoma-irt situ or dysplastic components that were MSS. The MSI-L and MSS f orms of gastric carcinoma all showed predominantly unmethylated hll;hMLH1 p romoter, positive hMLH1 protein and high hMLH1 mRNA level. On the other han d, hMSH2 protein was expressed in all of the tumors irrespective of the MSI status. Our results suggest that high-frequency MSI in sporadic gastric ca ncer is mostly due to epigenetic inactivation of hMLH1 in association with promoter methylation, and the loss of hMLH1 protein is a significant event in the development of invasive tumor.