Global DNA Methylation and Hydroxymethylation Differ in Hepatocellular‐ and Cholangio‐Carcinoma and Relate to Survival Rate

Abstract

DNA hydroxymethylation has been recently recognized as a novel epigenetic mark. Primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), are highly prevalent but epigenetically poorly characterized. Aims were to determine by a LC/MS/MS method methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) content in HCC and CC tissues as compared with homologous non‐neoplastic tissues and to analyze the survival rate according to mCyt and hmCyt levels in peripheral blood mononuclear cells (PBMCs) DNA. Thirty‐one HCC and 16 CC patients participated to the study; mCyt content was significantly lower in HCC than CC tissues (3.97% vs 5.26% respectively, p<0.0001). HCC tissues showed a lower mCyt compared to non‐neoplastic tissues (3.97% vs 4.82% mCyt, respectively, p<0.0001). No such difference was instead detected for the comparison of CC and non‐neoplastic tissues. HmCyt was similar in HCC and CC tissues, while it was reduced in HCC and CC as compared to homologous non‐neoplastic tissues (0.044 vs 0.128, p<0.0001 for HCC and 0.030 vs 0.124, p=0.026 for CC).The survival rate at 48 months in liver cancer patients with PBMCs mCyt>5.59% was higher than in those with lower mCyt levels (p=0.034).DNA hypomethylation distinguishes HCC from CC while DNA hypo‐hydroxymethylation characterizes both HCC and CC. PBMCs DNA mCyt content >5.59% relates to a favorable outcome in primary liver cancers.