Microsatellite Instability and Promoter Methylation of hMLH1 in Sporadic Gastric Carcinoma

ABSTRACT

BACKGROUND: An aberrant function of the mismatch repair system has been reported to underlie carcinogenesis in several tumors, including colorectal and gastric carcinomas, and to induce the typical genotype of microsatellite instability (MSI). PURPOSE: We aimed to determine the frequency of MSI in early-onset sporadic gastric carcinoma and elucidate the role of promoter methylation in hMLH1 as the mechanism of MSI. MATENRIALS AND METHODS: Thirty-six early-onset sporadic gastric carcinomas were analyzed to determine the status of MSI and the frequency of methylation of the promoter region in hMLH1. MSI was determined using five markers recommended by NCI MSI-H (high), MSI-L (low), and MSS (Microsatellite stable). Methylation specific PCR (MSP) and direct automated genomic sequencing analysis with DNA modified by sodium bisulfite have been performed to confirm promoter region methylation. All the data were analyzed regarding characteristics of molecular changes, and clinicopathologic variables. RESULTS: The microsatellite status was determined as MSI-H in five cases (13.8%), MSI-L in 13 cases (36.1%), and MSS in 18 cases (50.0%). hMLH1 was methylated in seven cases (19.4%). In all cases of MSI-H, promoter of hMLH1 was methylated, and in two of the 13 cases of MSI-L, hMLH1 promoter methylation was identified. Methylation was not found in any cases of MSS. Promoter methylation in hMLH1 was significantly correlated with MSI status (P<0.001). We could not find any relationship between MSI and clinicopathologic parameters. CONCLUSION: These results suggest that an abnormal function of the mismatch repair system may be associated with gastric carcinogenesis in more than 10% of early-onset gastric carcinomas and MSI appeared to be closely related to the promoter methylation in hMLH1.