Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma

<jats:sec> <jats:title/> <jats:p> <jats:bold>Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human liver tissue specimens. A total of 176 liver tissues, including 77 pairs of HCCs and matching noncancerous liver and 22 normal livers, were analyzed for methylation. Methylation of 19 epigenetic markers was quantified, and the results were correlated with different disease states and the presence or absence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Based on methylation profiles, the 19 loci were categorized into 3 groups. Normal liver tissues showed methylation primarily in group 1 loci (</jats:bold> <jats:bold> HIC </jats:bold>-<jats:bold> 1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> CASP8 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> GSTP1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> SOCS1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> RASSF1A </jats:bold> <jats:bold>,</jats:bold> <jats:bold> p16 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> APC </jats:bold> <jats:bold>), which was significantly higher than group 2 (</jats:bold> <jats:bold> CDH1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> RUNX3 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> RIZ1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> SFRP2 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> MINT31 </jats:bold> <jats:bold>) and group 3 markers (</jats:bold> <jats:bold> COX2 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> MINT1 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> CACNA1G </jats:bold> <jats:bold>,</jats:bold> <jats:bold> RASSF2 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> MINT2 </jats:bold> <jats:bold>,</jats:bold> <jats:bold> Reprimo </jats:bold> <jats:bold>,</jats:bold> <jats:bold> DCC </jats:bold> <jats:bold>) (</jats:bold> <jats:bold> P </jats:bold> <jats:bold>< 0.0001). Noncancerous livers demonstrated increased methylation in both group 1 and group 2 loci. Me ...