Genome-wide DNA methylation and gene expression profiles analysis show novel regulatory pathways in alcohol-related hepatocellular carcinoma

Chronic alcohol consumption is a dietary habit associated to cancer and in particular to hepatocellular carcinoma (HCC) but the mechanisms of alcohol-related liver carcinogenesis are still incompletely understood. Alcohol is known to interfere with one-carbon metabolism, the methyl transfer reactions occurring in the liver, and consequently with DNA methylation, one of the main epigenetic features related to cancer development. Aim of the present study was to define a possible role for DNA methylation in alcohol-related HCC in the absence of confounding factors, i.e. mainly hepatitis infections (HBV and HCV). We performed array-based genome-wide promoter DNA methylation and gene expression profiles in HCC tissue compared to homologous tumor-free liver tissue in eight patients undergoing curative surgery. The merging of DNA methylation and gene expression data allowed the detection of 160 hypermethylated-repressed, 31 hypomethylated -induced, 50 hypermethylated-induced and 56 hypomethylated-repressed genes. Among the hypermethylated-repressed genes we identified several candidate tumor-suppressor genes, six retinol metabolism genes (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22 and RDH16) and SHMT1 a key gene of one-carbon metabolism. In alcohol-related HCC DNA methylation at promoter site appears to regulate the expression of genes involved in retinol and one-carbon metabolism