hMLH1 Gene Promoter Methylation is the Major Cause of Microsatellite Instability in Gastric Cancer

Malfalda Pinto
Instituto de Patologia e Imunologia Molecular da Universidade do Porto;

Mutation of DNA mismatch repair genes has rarely been documented in sporadic gastric carcinoma with microsatellite instability (MIN) (1). In sporadic colorectal carcinoma, as well as in sporadic gastric carcinoma, hMLH1 promoter methylation associated with protein loss is found in the majority of MIN cases (2,3,4). We searched for microsatellite instability in a series of 152 thoroughly studied cases of sporadic gastric carcinoma with 5 or 6 microsatellite loci and/or BAT26, using polymerase chain reaction and electrophoresis. Thirty-five cases (23.0%) were positive for MIN.

We analyzed 21 tumors, randomly selected from the series referred above, stratified into 14 MIN positive (MIN+) and 7 MIN negative (MIN-), for mutations in the repeat sequences of TGFßRII, BAX and IGFIIR genes, and for hMLH1 promoter methylation. Mutations in TGFßRII occurred in 78.6% of the MIN+ tumors. BAX and IGFIIR mutations occurred, respectively, in 28.6% and 35.7% of MIN+ cases. None of the MIN- tumors presented mutations in the repeat sequences of these genes.

We found that hypermethylation of the CpG island in the hMLH1 promoter region was present in 78.6% of MIN+ sporadic gastric tumors. On the other hand, all MIN- gastric carcinomas showed unmethylated hMLH1 promoter. It was observed that all cases with IGFIIR mutation showed aberrant methylation. The same association does not hold true for BAX and TGFßRII genes. These results suggest that MIN in gastric cancer is mostly due to epigenetic inactivation of hMLH1 in association with promoter methylation. Moreover, the association between this promoter methylation and IGFIIR mutation needs to be further exploited.


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3 Herman, J.G. et al., Proc. Natl. Acad. Sci .USA; 95: 6870-6875, 1998.

4 Veigl, M.L. et al., Proc. Nat1. Acad. Sci. USA; 95: 8698-8702, l998.