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2014, Number 5

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Ann Hepatol 2014; 13 (5)

Promotor methylation: Does it affect response to therapy in chronic hepatitis C (G4) or fibrosis?

Zekri AN, Raafat AM, Elmasry S, Bahnassy AA, Saad Y, Dabaon HA, El-Kassas M, Shousha HI, Nassar AA, EL-Dosouky MA, Hussein N

Language: English
References: 22
Page: 518-524
PDF size: 102.80 Kb.


ABSTRACT

Background and aim. DNA methylation plays a critical role in the control of important cellular processes. The present study assessed the impact of promoter methylation (PM) of some genes on the antiviral response to antiviral therapy and it’s relation to the presence of fibrosis in HCV-4 infected patients from Egypt. Material and methods. Clinical, laboratory and histopathological data of 53 HCV-4 infected patients who were subjected to combined antiviral therapy were collected; patients were classified according to their response to treatment and the fibrosis status. The methylation profiles of the studied groups were determined using the following genes: APC, P14ARF, P73, DAPK, RASSF1A, and O6MGMT in patients’ plasma. Results. O6MGMT and P73 showed the highest methylation frequencies (64.2 and 50.9%) while P14 showed the lowest frequency (34%). Sustained virological response (SVR) was 54.7%with no significant difference in clinico-pathological or laboratory features between the studied groups. PM of O6MGM was significantly higher in non-responders (p value 0.045) while DAPK showed high methylation levels in responders with no significance (p value: 0.09) andPM of RASSF1A was significantly related to mild fibrosis (p value: 0.019). No significant relations were reported between PM of any of the studied genes and patients’ features. Conclusion. PM of some Tumor Suppressor genes increases in chronic active HCV-4. However, only 06MGMT can be used as a predictor of antiviral response and RASSF1A as a marker of marked fibrosis in this small set of patients. An extended study, including more patients is required to validate the results of this preliminary study.


REFERENCES

  1. Mindie H. Nguyen and Emmet B. Keeffe. Prevalence and Treatment of Hepatitis C Virus Genotypes 4, 5, and 6. Clin Gastroentrolo Hepatol 2005; 3: 97-101.

  2. Elkady A, Tanaka Y, Kurbanov F, Sugauchi F, Sugiyama F, Khan M, Sayed A, et al. Genetic Variability of Hepatitis C Virus in South Egypt and its Possible Clinical Implication. J Med Virol 2009; 1023: 1015-23.

  3. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology (Baltimore, Md) 2004; 39: 1147-71.

  4. Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006; 55:1350-9.

  5. Robertson KD. DNA methylation and human disease. Nature Reviews Genetics 2005; 6: 597-610.

  6. Okamoto Y, Shinjo K, Shimizu Y, Tsuyoshi S, Yamao K, Wentao G, Makiko F, et al. Hepatitis virus infection affects DNA methylation in mice with humanized livers. Gastroenterology 2014; 146: 562–72.

  7. Iyer P, Zekri AR, Hung CW, Schiefelbein E, Ismail K, Hablas A, Seifeldin I, et al. Concordance of DNA methylation pattern in plasma and tumor DNA of Egyptian hepatocellular carcinoma patients. Experimental and Molecular Pathology 2010; 88: 107–11.

  8. Zekri ARN, Bahnasy A , Shoeab FEM, Elzahraa F, Mohamed W, El-Dahshan D, Ali F, et al. Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma. Journal of Advanced Research 2014; 5: 27-40.

  9. Baylin SB, Ohm JE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nature Reviews Cancer 2006; 6: 107–16.

  10. Issa J. CpG island methylator phenotype in cancer. Nature Reviews Cancer 2004; 4: 988-93.

  11. Yang B, Guo M, Herman JG, Clark DP. Aberrant Promoter Methylation Profiles of Tumor Suppressor Genes in Hepatocellular Carcinoma Materials and Methods. Am J Pathol 2003;163: 1101-7.

  12. Yu J, Ni M, Xu J, Zhang H, Gao B, Gu J, Chen J, et al. Methylation profiling of twenty promoter-CpG islands of genes which may contribute to hepatocellular carcinogenesis. BMC Cancer 2002; 2: 29.

  13. Braakhuis BJM, Tabor MP, Kummer JA, Brakenhoff RH. A Genetic Explanation of Slaughter’s Concept of Field Cancerization: Evidence and Clinical Implications A Genetic Explanation of Slaughter’s Concept of Field Cancerization: Evidence and clinical implications. Cancer Research 2003; 63: 1727-30.

  14. Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez N, Vilaythong J, Houlihan P, et al. MGMT promoter methylation and field defect in sporadic colorectal cancer. Journal of the National Cancer Institute 2005; 97: 1330-8.

  15. Zekri AE-RN, Nassar AA-M, El-Din El-Rouby MN, Shousha H, Barakat A, El-Desouky E, Zayed N, et al. Disease progression from chronic hepatitis C to cirrhosis and hepatocellular carcinoma is associated with increasing DNA promoter methylation. Asian Pacific Journal of Cancer Prevention. APJCP 2013; 14: 6721-6.

  16. Li Z, Zhang H, Yang J, Hao T, Li S. Promoter hypermethylation of DNA damage response genes in hepatocellular carcinoma. Cell Biology International 2012; 36: 427-32.

  17. Di Gioia S, Bianchi P, Destro A, Grizzi F, Malesci A, Luigi L, Massimo L, et al. Quantitative evaluation of RASSF1A methylation in the non-lesional, regenerative and neoplastic liver. BMC Cancer 2006;6:89.

  18. Matsukura S, Soejima H, Nakagawachi T,Yakushiji H, Ogawa A, Fukuhara M, Miyazaki K, et al. CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. British Journal of Cancer 2003; 88: 521-9.

  19. Matsumura T, Makino R, Mitamura K. Frequent Down-Regulation of E-cadherin by Genetic and Epigenetic Changes in the Malignant Progression of Hepatocellular Carcinomas. Clinical Cancer Research 2001; 7: 594-9.

  20. Nomoto S, Kinoshita T, Kato K, Otani S, Kasuya H, Takeda S, Kanazumi N, et al. Hypermethylation of multiple genes as clonal markers in multicentric hepatocellular carcinoma. British Journal of Cancer 2007; 97: 1260-5.

  21. Saiz A, Anzola M, Cuevas N, Lo M, Martý M, Jose J. p14 ARF gene alterations in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2004; 16: 19-26.

  22. Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek M, Garrett M, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 1076-87.




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