title: RASSF1A and DOK1 Promoter Methylation Levels in Hepatocellular Carcinoma, Cirrhotic and Non-Cirrhotic Liver, and Correlation with Liver Cancer in Brazilian Patients.
abstract: Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (<40 years) patients, and higher in moderately differentiated than in poorly differentiated tumors (p < 0.05). Our results reinforce the hypothesis that hypermethylation of RASSF1A and DOK1 contributes to hepatocarcinogenesis and is associated to clinicopathological characteristics. RASSF1A and DOK1 promoter hypermethylation may be a valuable biomarker for early diagnosis of HCC and a potential molecular target for epigenetic-based therapy.
authors.affiliation: Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Oscar C
authors.initials: OC
authors.lastname: Araújo
authors.affiliation: Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Agatha S
authors.initials: AS
authors.lastname: Rosa
authors.affiliation: Department of Pathology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Arlete
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Christian
authors.initials: C
authors.lastname: Niel
authors.affiliation: Hepatology Division, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cristiane A
authors.initials: CA
authors.lastname: Villela-Nogueira
authors.affiliation: Department of Pathology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Vera
authors.initials: V
authors.lastname: Pannain
authors.affiliation: Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Araujo
mesh_terms: D000328:Adult; D000368:Aged; D001938:Brazil; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D010750:Phosphoproteins; C411762:RASSF1 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins