title: Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is one of the most frequent human cancers and a major cause of cancer-related death worldwide. The major risk factors for developing HCC are infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcoholism, and aflatoxins; however, critical gene targets remain largely unknown. Herein, we sought to establish DNA methylation patterns in HCC and corresponding cirrhotic tissues and to identify DNA methylation changes associated with major risk factors.
  
  
  METHODS
  We have established assays for quantitative analysis of DNA methylation levels in a panel of seven cancer-associated genes and repetitive elements, and combined these assays with a series of HCC tumors, associated with major risk factors, collected from two different geographical areas.
  
  
  RESULTS
  We found a high frequency of aberrant hypermethylation of specific genes (RASSF1A, GSTP1, CHRNA3, and DOK1) in HCC tumors as compared to control cirrhotic or normal liver tissues, suggesting that aberrant hypermethylation exhibits non-random and tumor-specific patterns in HCC. Importantly, our analysis revealed an association between alcohol intake and the hypomethylation of MGMT and between hypermethylation of GSTP1 and HBV infection, indicating that hypermethylation of the genes analyzed in HCC tumors exhibits remarkably distinct patterns depending on associated risk factors.
  
  
  CONCLUSIONS
  This study identifies aberrant DNA methylation of specific cellular genes in HCC and the major risk factors associated with these changes, providing information that could be exploited for biomarker discovery in clinics and molecular epidemiology.
authors.affiliation: Epigenetics Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lambert
authors.forename: Anupam
authors.initials: A
authors.lastname: Paliwal
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaissière
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chemin
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Bakary
authors.initials: B
authors.lastname: Sylla
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000235:genetics*; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006509:Hepatitis B / Q000150:complications*; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D051549:Glutathione S-Transferase pi; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011978:Receptors, Nicotinic; D025521:Tumor Suppressor Proteins; C489560:DOK1 protein, human; C411762:RASSF1 protein, human; C496556:GSTP1 protein, human