MICROSATELLITE INSTABILITY AND LOSS OF HETEROZYGOSITY AT DNA MISMATCHREPAIR GENE LOCI OCCURS DURING HEPATIC CARCINOGENESIS

DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicat ed in a variety of gastrointestinal and other turners; however, its ro le in hepatocellular carcinoma (HCC) has not been assessed. Formalin-f ixed, paraffin-embedded archival pathology tissues from 46 primary liv er tumors were studied by microdissection and microsatellite analysis of extracted DNA to assess the degree of microsatellite instability, a marker of defective mismatch repair, and to determine the extent and timing of allelic loss of two DNA mismatch repair genes, human Mut S h omologue-2 (hMSH2) and human Mut L homologue-1 (hMLH1), and the tumor suppressor genes adenomatous polyposis coli gene (APC), p53, and DPC4. Microsatellite instability was detected in 16 of the tumors (34.8%). Loss of heterozygosity at microsatellites linked to the DNA mismatch r epair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the patt ern of allelic loss was uniform in 8 of these 9 tumors, suggesting tha t clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was as sociated with marked allelic heterogeneity. There was relatively infre quent loss of APC, p53, or DPC4 loci that appeared unrelated to loss o f hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hML H1 gene loci, and the associated microsatellite instability in premali gnant hepatic tissues suggests a possible causal role in hepatic carci nogenesis in a subset of hepatomas.