OBJECTIVE To study the relationship among microsatellite instability (MSI), frameshift mutations (FM) of the transforming growth factor β receptor Ⅱ (TGFβR Ⅱ), methylation state of the hMLH1 promoter and hMLH1 protein expression level in gastric cancers, and to explore their relationship to gastric carcinogenesis.METHODS DNA was isolated from 101 gastric specimens and 5 microsatellite loci were detected. PCR, electrophoresis on denatured polyacrylamide gels and silver staining were performed to detect the MSI. The FMs of TGFβR Ⅱ were also screened with the same method. HMLH1 methylation was analyzed by methylation specific PCR (MSP) and sequencing. HMLH1 protein expression was detected using immunohistochemistry.RESULTS The incidence of MSIs was 53.7% and 0% in the cancers and normal tissues, respectively, with the frequency of MSIs being significantly higher in the gastric cancers compared to the normal gastric tissues (P＜0.05). The frequency of hMLH1 methylation was 41.5%(17/41) in the gastric cancers and 0%(0/60) in the normal group. Decreased hMLH1 expression was observed in 94.1%(16/17) of cases exhibiting methylation. FMs of TGFβR Ⅱ were identified in 5 (62.5%) of the 8 samples with MSIH. In contrast, FMs were not found in MSI-L or microsatellite stable (MSS) cases.CONCLUSION MSIs and FMs of TGFβR Ⅱ may play an important role in gastric carcinogenesis. HMLH1 methylation is an important modification of the DNA which results in inactivation of hMLH1 and mismatch repair defects which lead to MSIs and FMs of TGFβR Ⅱ.