Methylation of the hMLH1 promoter in familial gastric cancer with microsatellite instability

Microsatellite instability (MSI), which is recognized as an important mecha nism in tumorigenesis, has been reported in familiar gastric cancers (FGC), However, genetic defects responsible for this phenotype, that is, mutation s in mismatch-repair genes such as hMLH1 and hMSH2, have not been detected in most FGC cases. Earlier studies have shown that: the promoter region of the hMLH1 gene was methylated in some sporadic colorectal and endometrial c ancers. To determine how FGC acquire MSI, we examined the MSI status, hMLH1 -protein expression and methylation status of the hMLH1-promoter region in FCC cases. Out of 9 cancers, 6 from 8 FGC kindreds showed MSI at one or mor e loci; no germline mutations in the hMLH1 or hMSH2 genes were detected; 4 cancers exhibiting MSI displayed aberrant: hMLH1 expression: complete loss in one, decreased level in another, and partially staining pattern in the r emaining 2, Methylation in the hMLH1-promoter region was found in these 4 c ases. In contrast, the cancers displaying hMLH1-protein expression were not methylated in the hMLH1-promoter region. Our data show a significant assoc iation between the absence of hMLH1 expression and methylation of its promo ter in FGC cases with MSI, This suggests that the mechanism of inactivation of hMLH1 is epigenetic and that there are other genes responsible for FGC. (C) 2000 Wiley-Liss, Inc.