Infrequent widespread microsatellite instability in hepatocellular carcinomas

Widespread or high-frequency microsatellite instability (MSI) due to the de fective DNA mismatch repair (MMR) occurs in the majority of hereditary non- polyposis colorectal cancer and a subset of sporadic malignant tumors. The incidence of MSI and underlying DNA MMR defects have been well characterize d in gastrointestinal carcinogenesis, but not in hepatocarcinogenesis. To a ddress the issue, we analyzed 55 Japanese hepatocellular carcinomas using s everal indicators of DNA MMR defects, such as microsatellite analysis, loss of heterozygosity (LOH) and mutation analysis of MMR genes, methylation of hMLH1 promoter, and frameshift mutations of mononucleotide repeat sequence s within possible target genes. Mutation of beta 2-microglobulin gene, whic h is presumably involved in MSI-positive tumor cell escape from immune surv eillance was also examined. Some of these analyses were also carried out in 9 human liver cancer cell lines. None of the 3 quasi-monomorphic mononucle otide markers sensitive for MSI, BAT26, BAT25, and BAT34C4 presented shorte ned unstable alleles in any of the carcinoma, cirrhosis, chronic hepatitis tissues, or cell lines, LOH at MMR genes was infrequent (4.4 similar to 7.1 %), and no mutations were detected. Neither hMLH1 hypermethylation nor fram eshift mutation in the target genes was detected. No mutations were found i n beta 2-microglobulin. Widespread MSI due to the defective DNA MMR appears to play little if any part in Japanese hepatocarcinogenesis.