| Research Abstract |
The aim of the research project is to clarify the clinicopathological characteristics of human gastric carcinomas with microsatellite instability as well as to analyze the molecular inactivation mechanisms for mismatch repair system within these cancers.
The investigator established a routine microsatellite analysis system using conventional histopathological specimens. Extracted gastric cancers with microsatellite instability were subjected for the mutation of mismatch repair system genes (hMLH1, hMSH2) by PCR-SSCP and direct sequencing. Expression of mismatch repair immunohistochmistry using specific monoclonal antibodies. Methylation of promoter CpG sequences in these repair genes were analyzed by methylation specific PCR method which was established and optimized for the DNA extracted from hitopathological paraffin sections.
From the routine microsatellite analysis over 1000 gastric cancer biopsies, the investigator clarified the clinicopathological characteristics of the gastric carcinomas with micorosatellite instability as following, (1) they share about 6% of overall gastric carcinomas, (2) most of the tumors are protruding type well-differentiated adenocarcinomas, (3) patients with gastric tumors with microsatellite instability prone to have multiple tumors within the same stomach or other gastrointestinal tracts. Although mutation analysis of mismatch repair genes within these tumors failed to demonstrate 2-hit genetic inactivation of the genes, most of the tumors demonstrated loss of expression of hMLH1 along with the hypermethylation of its promoter CpG sequences.
These results suggest that epigenetic inactivation of one of the mismatch repair system gene, hMLH1, may have the crucial role in the carcinogenesis of gastric carcinomas with microsatellite instability.
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