Frequent chromosomal instability but no microsatellite instability in hepatocellular carcinomas.
Microsatellite instability (MSI) phenotype, caused by a deficiency of DNA mismatch repair genes, has been detected in a subset of tumors in the gastrointestinal tract. However, it is not clear how MSI is involved in the tumorigenesis of hepatocellular carcinomas (HCC). Results with HCC are controversial, with positive results published with American and European tumors, but negative with Japanese tumors. We report the absence of MSI in 39 Korean HCCs after analysis with 6 mononucleotide- and over 150 dinucleotide-repeat markers. Only one such dinucleotide-repeat (D2S213) exhibited a reproducible shift in mobility, representing a somatic mutation present in only some of the tumor cells. This may be the result of a spontaneous error of replication due to the intrinsic mutability of these unstable sequences and without any connection to true genomic instability. In support of this interpretation, no frameshift mutations were found at the coding repeats of target genes for the microsatellite mutator phenotype including TGF-betaRII, BAX, hMSH3, and hMSH6. In contrast, we observed frequent allelic losses on chromosomes 4q, 8p, 16q, and 17p by the analysis of dinucleotide repeats (microallelotyping), reflecting a high degree of tumor chromosomal instability, which was significantly associated to the tumor differentiation (p=0.036, Fisher's exact test). These results suggest that, unlike chromosomal instability, widespread MSI plays no role in the development or progression of HCC.
The Burnham Institute, La Jolla, CA 92037, USA. zpiao@burnham.org
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Piao
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Kim
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Malkhosyan
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Park
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008113:Liver Neoplasms / Q000150:complications / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009857:Oncogenes
D004273:DNA, Neoplasm