Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis

Abstract

DNA mismatch repair is an important mechanism involved in maintaining the fidelity of genomic DNA. Defective DNA mismatch repair is implicated in a variety of gastrointestinal and other tumors; however, its role in hepatocellular carcinoma (HCC) has not been assessed. Formalin-fixed, paraffin-embedded archival pathology tissues from 46 primary liver 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 homologue-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 repair genes, hMSH2 and/or hMLH1, was found in 9 cases (19.6%), usually in association with microsatellite instability. Importantly, the pattern of allelic loss was uniform in 8 of these 9 tumors, suggesting that clonal loss had occurred. Moreover, loss at these loci also occurred in nonmalignant tissue adjacent to 4 of these tumors, where it was associated with marked allelic heterogeneity. There was relatively infrequent loss of APC, p53, or DPC4 loci that appeared unrelated to loss of hMSH2 or hMLH1 gene loci. Loss of heterozygosity at hMSH2 and/or hMLH1 gene loci, and the associated microsatellite instability in premalignant hepatic tissues suggests a possible causal role in hepatic carcinogenesis in a subset of hepatomas. (HEPATOLOGY 1998;28:90-97.)

The vascular profile of regenerative and dysplastic nodules of the cirrhotic liver: Implications for diagnosis and classification

“…To date there are no morphological or phenotypic clues indicating that these lesions are premalignant. 23 As previously mentioned, however, some of them are in fact monoclonal 21 ; undoubtedly, only the molecular characterization of individual hepatocellular nodules 25,26 will contribute to establish which lesions are regenerative or neoplastic. The correlation of basic biological analysis with morphophenotypic features is then expected to provide helpful information of clinical significance.…”

EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer

“…Metastatic melanoma tissue and matched blood or normal skin tissue were obtained from 20 patients and DNA isolated as reported previously (Indsto et al, 1998). DNA was extracted from matched normal liver and hepatocellular carcinoma tissue samples microdissected from 19 primary liver tumours (Macdonald et al, 1998). For AI analysis, paraffin-embedded breast cancer tissues and normal blood were obtained from 24 patients.…”

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…Concomitantly, pRb is functionally inactivated in a majority of HCCs (Malumbres and Barbacid, 2001; Thorgeirsson and Grisham, 2002;Edamoto et al, 2003). Approximately, 40% of HCCs display microsatellite instability (MSI) or inactivating mutations in the mismatch repair genes, hMSH2 and hMLH1 (Macdonald et al, 1998;Yamamoto et al, 2000). MSI is in turn associated with mutations in TGFb receptor type II (TBRII), M6P/IGFIIR and BAX genes.…”