ABERRANT DNA METHYLATION ON CHROMOSOME-16 IS AN EARLY EVENT IN HEPATOCARCINOGENESIS

In order to clarify the significance of DNA methylation in both earlie r and later stages of hepatocarcinogenesis, the DNA methylation state on chromosome 16, on which loss of heterozygosity (LOH) has frequently been detected in human hepatocellular carcinomas (HCCs), was examined . DNA from primary HCCs and tissues showing chronic hepatitis and live r cirrhosis, which are considered to be precancerous conditions, was a nalyzed by digestion with methylation-sensitive and non-sensitive rest riction enzymes. DNA hypermethylation at the D16S32, tyrosine aminotra nsferase (TAT) and D16S7 loci and hypomethylation at the D16S4 locus w ere detected in 18%, 58%, 20% and 48% of examined HCCs, respectively. Aberrant DNA methylation occurred more frequently in advanced HCCs tha n in early HCCs. Moreover, DNA hypermethylation at the D16S32, TAT and D16S7 loci was frequently observed in chronic hepatitis and liver cir rhosis. The incidence of DNA hypermethylation was higher than that of LOH (42% at the TAT locus). These data suggest that DNA hypermethylati on might predispose the locus to allelic loss. Aberrant DNA methylatio n is a significant change which may participate in the early developme ntal stages of HCCs.