Widespread or high-frequency
microsatellite instability (MSI) due to the defective 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 characterized in gastrointestinal
carcinogenesis, but not in hepatocarcinogenesis. To address the issue, we analyzed 55 Japanese
hepatocellular carcinomas using several 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 sequences within possible target genes. Mutation of beta2-microglobulin gene, which is presumably involved in MSI-positive
tumor cell escape from immune surveillance was also examined. Some of these analyses were also carried out in 9 human
liver cancer cell lines. None of the 3 quasi-monomorphic mononucleotide markers sensitive for MSI, BAT26, BAT25, and BAT34C4 presented shortened unstable alleles in any of the
carcinoma,
cirrhosis,
chronic hepatitis tissues, or cell lines. LOH at MMR genes was infrequent (4.4 approximately 7.1%), and no mutations were detected. Neither hMLH1 hypermethylation nor frameshift mutation in the target genes was detected. No mutations were found in beta2-microglobulin. Widespread MSI due to the defective
DNA MMR appears to play little if any part in Japanese hepatocarcinogenesis.