DNA Methylation Status in Chronic Liver Disease and Hepatocellular Carcinoma

Abstract

Alterations of DNA methylation are among the most consistent epigenetic changes observed in human cancers. In comparison with normal liver tissue, such alterations occur in a genome-wide manner in non-cancerous liver tissue showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions. DNA methylation alterations at the precancerous stage may rapidly generate more malignant cancers. Multiple tumor-related genes, such as the E-cadherin, HIC-1, p16, p15, TMS1/ASC, TIMP3, MGMT, RASSF1A 1, 14-3-3-σ, and SOCS-1 genes, are silenced by DNA hypermethylation in hepatocellular carcinomas (HCCs). Expression of DNA methyltransferase (DNMT) 1 is significantly higher in non-cancerous liver tissue showing chronic hepatitis or cirrhosis than in normal liver tissue. DNMT1 overexpression is also correlated with poorer tumor differentiation, portal vein involvement and intrahepatic metastasis of HCCs, and poorer patient outcome. On the other hand, overexpression of DNMT3b4, an inactive splice variant of DNMT3b, may lead to chromosomal instability through induction of DNA hypomethylation in pericentromeric satellite regions during hepatocarcinogenesis. Genome-wide DNA methylation profiling provides optimal indicators for carcinogenetic risk estimation in patients with chronic liver diseases, and for prognostication in patients with HCCs. With the intention of controlling hepatocarcinogenesis from the chronic liver disease stage, translational epigenetics have come of age.