Methylation of hMLH1 in a population-based series of endometrial carcinomas

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI, It has recently been demon strated that hypermethylation of the hMLH1 promoter region is associated,vi th MSI and appears to be a common mechanism for gene inactivation. For endo metrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequenc y and prognostic significance of hypermethylation of the hMLH1 and hMSH2 ge nes in conjunction with hMLH1 protein expression in a prospective and popul ation-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylati on of hMLH1 was found in 23% of tumors with conclusive results, whereas met hylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was s ignificantly correlated with MSI (P < 0.001), Loss of nuclear staining of h MLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%), Of the 14 MSI-positive tumor s that were also methylated, all but 1 (93%) showed a loss of nuclear expre ssion of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 m ethylation were aneuploid (P for both less than or equal to 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated wit h lack of p53 overexpression (P for both less than or equal to 0.05), Nucle ar hMLH1 staining and hMLH1 methylation did not significantly influence sur vival. In conclusion, hMLH1 methylation was common and was significantly co rrelated with loss of hMLH1 protein expression, MSI, diploid tumors, and la ck of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.