title: Aberrant DNA methylation of imprinted loci in hepatocellular carcinoma and after in vitro exposure to common risk factors.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is among the most frequent human malignancies and a major cause of cancer-related death worldwide. It is characterized by late detection and fast progression, and it is believed that epigenetic disruption may be one of the molecular mechanisms leading to hepatocarcinogenesis. Previous studies from our group revealed that HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression. Imprinted genes are mono-allelically expressed in a parent-of-origin-dependent manner and have been suggested to be more susceptible to deregulation in cancer. To test this notion, we performed a targeted analysis of DNA methylation in known imprinted genes, using HCC samples and in vitro models of carcinogenic exposure.
  
  
  RESULTS
  Analysis of HCC DNA methylation in two independent datasets showed that differentially methylated loci are significantly enriched in imprinted genes. Most of the promoters of imprinted genes were found hypomethylated in HCC tumors compared to surrounding tissues, contrasting with the frequent promoter hypermethylation observed in tumors. We next investigated the status of methylation of the imprinting control region (ICR) of different imprinted clusters and found that the 15q11-13 ICR was significantly hypomethylated in tumors relative to their surrounding tissues. In addition, expression of imprinted genes within this cluster was frequently deregulated in a gene-specific manner, suggesting distinct mechanisms of regulation in this region. Finally, primary human hepatocytes and hepatocyte-like HepaRG cells displayed higher methylation variability in certain imprinted loci after natural hepatitis B virus (HBV) infection and after lipid accumulation, respectively.
  
  
  CONCLUSIONS
  The methylation status of a large panel of imprinted genes was found deregulated in HCC, suggesting a major role of this mechanism during hepatocarcinogenesis. In vitro models support the hypothesis of imprinted gene methylation as a potential marker of environmental exposures.
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.|Current address: Epissage alternatif et progression tumorale, Centre de Recherche en Cancérologie de Lyon (CRCL), 28 rue Laennec, 69008 Lyon, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Pierre-Benoit
authors.initials: PB
authors.lastname: Ancey
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Davide Degli
authors.initials: DD
authors.lastname: Esposti
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cros
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Athena
authors.initials: A
authors.lastname: Sklias
authors.affiliation: Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: INSERM U871, Molecular physiopathology and new treatments of viral hepatitis, Centre de recherche en cancérologie (CRCL), 151 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, 69008 Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
keywords: Imprinting; Liver cancer; Methylome; Promoter methylation