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Disease Progression from Chronic Hepatitis C to Cirrhosis and Hepatocellular Carcinoma is Associated with Increasing DNA Promoter Methylation

  • Zekri, Abd El-Rahman Nabawy (Virology and Immunology, Faculty of Science, Ain Shams University) ;
  • Nassar, Auhood Abdel-Monem (Virology and Immunology, Faculty of Science, Ain Shams University) ;
  • El-Rouby, Mahmoud Nour El-Din (Virology and Immunology, Faculty of Science, Ain Shams University) ;
  • Shousha, Hend Ibrahim (Hepatogastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University) ;
  • Barakat, Ahmed Barakat (Microbiology (Virology), Faculty of Science, Ain Shams University) ;
  • El-Desouky, Eman Desouky (Epidemiology and Biostatistics, National Cancer Institute, Faculty of Science, Ain Shams University) ;
  • Zayed, Naglaa Ali (Hepatogastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University) ;
  • Ahmed, Ola Sayed (Virology and Immunology, Faculty of Science, Ain Shams University) ;
  • Youssef, Amira Salah El-Din (Virology and Immunology, Faculty of Science, Ain Shams University) ;
  • Kaseb, Ahmed Omar (Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center) ;
  • El-Aziz, Ashraf Omar Abd (Hepatogastroenterology and Endemic Medicine, Faculty of Medicine, Cairo University) ;
  • Bahnassy, Abeer Ahmed (Virology and Immunology, Faculty of Science, Ain Shams University)
  • Published : 2013.11.30

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. Materials and 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.

Keywords

HCV;cirrhosis;hepatocellular carcinoma;tumor suppressor gene methylation;progression

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