Role of hMLH1 Gene Hypermethylation in Endometrial Carcinogenesis

Inactivation of the hMLH1 gene by promoter hypermethylation is one of the major mechanisms that induces the microsatellite instability phenotype in endometrial cancers. The aim of the present study was to examine the methylation profile of a large number of CpG sites spread over the hMLH1 promoter in endometrial cancers, as well as in normal endometria, and to investigate the correlation with protein expression and MSI phenotype. We found that the hMLH1 promoter is frequently methylated in endometrial cancers. Surprisingly, the histologically normal endometrium of patients with endometrial cancers also exhibited frequent hypermethylation of hMLHl promoter and with a similar profile of methylation to that in cancer lesions. These findings suggest that hypermethylation of the hMLH1 gene is the early step for endometrial carcinogenesis, supporting the concept that epigenetic changes in DNA mismatch repair genes are the initial events that trigger the genetic alterations involved in endometrial carcinogenesis. In addition, irregular methylation of the hMLH1 promoter may be a useful molecular marker with which to screen or diagnose precancerous and early endometrial malignancies.