title: Disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma is associated with increasing DNA promoter methylation.
abstract: BACKGROUND
  Changes in DNA methylation patterns are believed to be early events in hepatocarcinogenesis. A better understanding of methylation states and how they correlate with disease progression will aid in finding potential strategies for early detection of HCC. The aim of our study was to analyze the methylation frequency of tumor suppressor genes, P14, P15, and P73, and a mismatch repair gene (O6MGMT) in HCV related chronic liver disease and HCC to identify candidate epigenetic biomarkers for HCC prediction.
  
  
  METHODS
  516 Egyptian patients with HCV-related liver disease were recruited from Kasr Alaini multidisciplinary HCC clinic from April 2010 to January 2012. Subjects were divided into 4 different clinically defined groups - HCC group (n=208), liver cirrhosis group (n=108), chronic hepatitis C group (n=100), and control group (n=100) - to analyze the methylation status of the target genes in patient plasma using EpiTect Methyl qPCR Array technology. Methylation was considered to be hypermethylated if >10% and/or intermediately methylated if >60%.
  
  
  RESULTS
  In our series, a significant difference in the hypermethylation status of all studied genes was noted within the different stages of chronic liver disease and ultimately HCC. Hypermethylation of the P14 gene was detected in 100/208 (48.1%), 52/108 (48.1%), 16/100 (16%) and 8/100 (8%) among HCC, liver cirrhosis, chronic hepatitis and control groups, respectively, with a statistically significant difference between the studied groups (p-value 0.008). We also detected P15 hypermethylation in 92/208 (44.2%), 36/108 (33.3%), 20/100 (20%) and 4/100 (4%) , respectively (p-value 0.006). In addition, hypermethylation of P73 was detected in 136/208 (65.4%), 72/108 (66.7%), 32/100 (32%) and 4/100 (4%) (p-value <0.001). Also, we detected O6MGMT hypermethylation in 84/208 (40.4%), 60/108 (55.3%), 20/100 (20%) and 4/100 (4%), respectively (p value <0.001.
  
  
  CONCLUSIONS
  The epigenetic changes observed in this study indicate that HCC tumors exhibit specific DNA methylation signatures with potential clinical applications in diagnosis and prognosis. In addition, methylation frequency could be used to monitor whether a patient with chronic hepatitis C is likely to progress to liver cirrhosis or even HCC. We can conclude that methylation processes are not just early events in hepatocarcinogenesis but accumulate with progression to cancer.
authors.affiliation: Virology and Immunology, National Cancer Institute, Cairo University, Cairo, Egypt E-mail : ncizekri@yahoo.com.
authors.forename: Abd El-Rahman Nabawy
authors.initials: Ael-R
authors.lastname: Zekri
authors.forename: Auhood Abdel-Monem
authors.initials: AA
authors.lastname: Nassar
authors.forename: Mahmoud Nour
authors.initials: MN
authors.lastname: El-Din El-Rouby
authors.forename: Hend Ibrahim
authors.initials: HI
authors.lastname: Shousha
authors.forename: Ahmed Barakat
authors.initials: AB
authors.lastname: Barakat
authors.forename: Eman Desouky
authors.initials: ED
authors.lastname: El-Desouky
authors.forename: Naglaa Ali
authors.initials: NA
authors.lastname: Zayed
authors.forename: Ola Sayed
authors.initials: OS
authors.lastname: Ahmed
authors.forename: Amira Salah
authors.initials: AS
authors.lastname: El-Din Youssef
authors.forename: Ahmed Omar
authors.initials: AO
authors.lastname: Kaseb
authors.forename: Ashraf Omar
authors.initials: AO
authors.lastname: Abd El-Aziz
authors.forename: Abeer Ahmed
authors.initials: AA
authors.lastname: Bahnassy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000821:virology; D016022:Case-Control Studies; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000473:pathology* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology* / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins