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Clinical Epigenetics

, 7:43

First Online: 14 April 2015Received: 23 March 2015Accepted: 26 March 2015


BackgroundAlcohol is a well-known risk factor for hepatocellular carcinoma HCC, but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue.

ResultsAfter merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16, iron homeostasis HAMP, one-carbon metabolism SHMT1, and genes with a putative, newly identified function as tumor suppressors FAM107A, IGFALS, MT1G, MT1H, RNF180.

ConclusionsA genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC.

Due to the reversibility of epigenetic mechanisms by environmental-nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.

KeywordsAlcohol Candidate tumor-suppressor genes DNA methylation Epigenetics Gene expression array Hepatocellular carcinoma MeDIP-chip One-carbon metabolism Retinol metabolism AbbreviationsHCChepatocellular carcinoma


HBVhepatitis B virus

HCVhepatitis C virus

EBVEpstein-Barr virus


HIVhuman immunodeficiency virus type 1

CTcomputerized tomography

MRInuclear magnetic resonance imaging

PET-CTpositron emission tomography

ASTaspartate transaminase

ALTalanine transaminase

GGTgamma-glutamyl transpeptidase



INRAN Istituto Nazionale di Ricerca per gli Alimenti e la NutrizioneNational Institute for the Research on Foods and Nutrition

MeDIPmethylated DNA immunoprecipitation



ROIregion of interest

PANTHERProtein ANalysis THrough Evolutionary Relationship


Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0077-1 contains supplementary material, which is available to authorized users.

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Autor: Silvia Udali - Patrizia Guarini - Andrea Ruzzenente - Alberto Ferrarini - Alfredo Guglielmi - Valentina Lotto - Paola Tonon

Fuente: https://link.springer.com/

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