Aberrant p16INK4A methylation: Relation to viral related chronic liver disease and hepatocellular carcinoma

Fatma A. El-Mougy; Mohammed M. Youssef; Dalia A. Omran; Sahar A. Sharaf; Hany H. El-Sayed; Walaa A. Rabie; Elghobary A. Mohamed; Hany A. Elghobary

doi:10.4103/2278-330X.126498

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BENCH-PRESS : Original Article

03 (

); 001-004

doi:

10.4103/2278-330X.126498

Aberrant p16INK4A methylation: Relation to viral related chronic liver disease and hepatocellular carcinoma

Fatma A. El-Mougy¹, Mohammed M. Youssef², Dalia A. Omran^2,, Sahar A. Sharaf¹, Hany H. El-Sayed¹, Walaa A. Rabie¹, Elghobary A. Mohamed³, Hany A. Elghobary¹

1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo

2 Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Cairo

3 Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo

*Corresponding author: Dr. Dalia Omran. daliaomran2007@yahoo.com

Published: 2020-12-31

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Background: Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer related deaths. Several studies have shown that the tumor suppressor gene p16INK4A is frequently downregulated by aberrant methylation of the 5′-cytosine-phosphoguanine island within the promoter region. Aim: To find out the frequency of methylated p16INK4A in the peripheral blood of HCC and cirrhotic patients and to evaluate its role in hepatocarcinogenesis. Patients and Methods: This study was performed on 58 subjects: 30 HCC patients, 20 cirrhotic patients, and eight healthy volunteers. Methylation of p16INK4A was examined using methylation specific polymerase chain reaction (PCR) (MSP). Comparison of quantitative variables between the study groups was done using Mann-Whitney U test for independent samples when not normally distributed. For comparing categorical data, Chi-square (χ² ) test was performed. Exact test was used instead when the expected frequency was less than 5. Results: Methylation of p16INK4A was found in 6.7% of HCC patients, 5% of liver cirrhosis (LC) patients, and none of the healthy volunteers; 66.67% of the p16INK4A-methylated cases (2/3) were positive for anti-hepatitis C virus (HCV) antibodies (one of them had HCC). All HCC cases with aberrant p16INK4A methylation show very high serum alpha fetoprotein (AFP) level (9,080; 30,000 μg/mL). There were no significant associations between the status of p16INK4A methylation and tumor size. Conclusion: Hypermethylation of p16INK4A was found to be infrequent among Egyptian patients with HCC.

Keywords

Acknowledgment

We would like to thank Dr. Nabeel El Kady, Professor of Tropical Medicine, Cairo University for his contribution and continuous support throughout this work.

References

El-Serag HB, Rudolph. KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
Anwar WA, Khaled HM, Amra HA, El-Nezami H, Loffredo CA. Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: Possibilities for prevention. Mutat Res 2008;659:176-84.
Shiraz OB, Galehdari H, Yavarian M, Geramizadeh B. Possible down regulation of the p16 gene promoter in individuals with hepatocellular carcinoma. Hepat Mon 2011;11:719-23.
Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31:339-46.
Matsuda Y. Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. World J Gastroenterol 2008;14:1734-40.
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5 CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995;1:686-92.
Zang JJ, Xie F, Xu JF, Qin YY, Shen RX, Yang JM, et al. P16 gene hypermethylation and hepatocellular carcinoma: A systematic review and meta-analysis. World J Gastroenterol 2011;17:3043-8.
Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European association for the study of the liver. J Hepatol 2001;35:421-30.
Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994;22:2990-7.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR. A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821-6.
Song N, Tan W, Xing D, Lin D. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: A case control study in china. Carcinogenesis 2001;22:11-6.
Wong IH, Zhang J, Lai PB, Lau WY, Lo YM. Quantitative analysis of tumor-derived methylated p16INK4a sequences in plasma, serum, and blood cells of hepatocellular carcinoma patients. Clin Cancer Res 2003;9:1047-52.
Tarao K, Ohkawa S, Shimizu A, Harada M, Nakamura Y, Ito Y, et al. The male preponderance in incidence of hepatocellular carcinoma in cirrhotic patients may depend on the higher DNA synthetic activity of cirrhotic tissue in men. Cancer 1993;72:369-74.
Lui WY, Lin HL, Chau GY, Liu TY, Chi CW. Male predominance in hepatocellular carcinoma: New insight and a possible therapeutic alternative. Med Hypotheses 2000;55:348-50.
Kaneto H, Sasaki S, Yamamoto H, Itoh F, Toyota M, Suzuki H, et al. Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut 2001;48:372-7.
Li X, Hui AM, Sun L, Hasegawa K, Torzilli G, Minagawa M, et al. p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma. Clin Cancer Res 2004;10:7484-9.
Jung JK, Arora P, Pagano JS, Jang KL. Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1- CDK 4/6-pRb-E2F1 pathway. Cancer Res 2007;67:5771-8.
Ro¨cken C, Carl-McGrath S. Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis 2001;19:269-78.
Shen L, Ahuja N, Shen Y, Habib NA, Toyota M, Rashid A, et al. DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst 2002;94:755-61.
Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras-2 mutations and p16INK4A methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001;84:982-9.
Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis: A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology 2000;32:970-9.
Kim JR, Kim SY, Kim MJ, Kim JH. Alterations of CDKN2 (MTS1/p16INK4A) gene in paraffin-embedded tumor tissues of human stomach, lung, cervix and liver cancers. Exp Mol Med 1998;30:109-14.
Roncalli M, Bianchi P, Bruni B, Laghi L, Destro A, Di Gioia S, et al. Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Hepatology 2002;36:427-32.
Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancers patients. Cancer Res 1999;59:71-3.
Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends Genet 2000;16:168-74.
Wong IH, Johnson PJ, Lai PB, Lau WY, Lo YM. Tumor-derived epigenetic changes in the plasma and serum of liver cancer patients: Implications for cancer detection and monitoring. Ann N Y Acad Sci 2000;906:102-5.

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[1] El-Serag HB, Rudolph. KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.

[2] Anwar WA, Khaled HM, Amra HA, El-Nezami H, Loffredo CA. Changing pattern of hepatocellular carcinoma (HCC) and its risk factors in Egypt: Possibilities for prevention. Mutat Res 2008;659:176-84.

[3] Shiraz OB, Galehdari H, Yavarian M, Geramizadeh B. Possible down regulation of the p16 gene promoter in individuals with hepatocellular carcinoma. Hepat Mon 2011;11:719-23.

[4] Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31:339-46.

[5] Matsuda Y. Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma. World J Gastroenterol 2008;14:1734-40.

[6] Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5 CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995;1:686-92.

[7] Zang JJ, Xie F, Xu JF, Qin YY, Shen RX, Yang JM, et al. P16 gene hypermethylation and hepatocellular carcinoma: A systematic review and meta-analysis. World J Gastroenterol 2011;17:3043-8.

[8] Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European association for the study of the liver. J Hepatol 2001;35:421-30.

[9] Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994;22:2990-7.

[10] Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR. A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821-6.

[11] Song N, Tan W, Xing D, Lin D. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: A case control study in china. Carcinogenesis 2001;22:11-6.

[12] Wong IH, Zhang J, Lai PB, Lau WY, Lo YM. Quantitative analysis of tumor-derived methylated p16INK4a sequences in plasma, serum, and blood cells of hepatocellular carcinoma patients. Clin Cancer Res 2003;9:1047-52.

[13] Tarao K, Ohkawa S, Shimizu A, Harada M, Nakamura Y, Ito Y, et al. The male preponderance in incidence of hepatocellular carcinoma in cirrhotic patients may depend on the higher DNA synthetic activity of cirrhotic tissue in men. Cancer 1993;72:369-74.

[14] Lui WY, Lin HL, Chau GY, Liu TY, Chi CW. Male predominance in hepatocellular carcinoma: New insight and a possible therapeutic alternative. Med Hypotheses 2000;55:348-50.

[15] Kaneto H, Sasaki S, Yamamoto H, Itoh F, Toyota M, Suzuki H, et al. Detection of hypermethylation of the p16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus. Gut 2001;48:372-7.

[16] Li X, Hui AM, Sun L, Hasegawa K, Torzilli G, Minagawa M, et al. p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma. Clin Cancer Res 2004;10:7484-9.

[17] Jung JK, Arora P, Pagano JS, Jang KL. Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1- CDK 4/6-pRb-E2F1 pathway. Cancer Res 2007;67:5771-8.

[18] Ro¨cken C, Carl-McGrath S. Pathology and pathogenesis of hepatocellular carcinoma. Dig Dis 2001;19:269-78.

[19] Shen L, Ahuja N, Shen Y, Habib NA, Toyota M, Rashid A, et al. DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst 2002;94:755-61.

[20] Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras-2 mutations and p16INK4A methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001;84:982-9.

[21] Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis: A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology 2000;32:970-9.

[22] Kim JR, Kim SY, Kim MJ, Kim JH. Alterations of CDKN2 (MTS1/p16INK4A) gene in paraffin-embedded tumor tissues of human stomach, lung, cervix and liver cancers. Exp Mol Med 1998;30:109-14.

[23] Roncalli M, Bianchi P, Bruni B, Laghi L, Destro A, Di Gioia S, et al. Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Hepatology 2002;36:427-32.

[24] Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancers patients. Cancer Res 1999;59:71-3.

[25] Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends Genet 2000;16:168-74.

[26] Wong IH, Johnson PJ, Lai PB, Lau WY, Lo YM. Tumor-derived epigenetic changes in the plasma and serum of liver cancer patients: Implications for cancer detection and monitoring. Ann N Y Acad Sci 2000;906:102-5.

Aberrant p16INK4A methylation: Relation to viral related chronic liver disease and hepatocellular carcinoma

Abstract

Abstract

Keywords

Acknowledgment

References

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