Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis

Background and Aim: Chronic hepatitis B virus (HBV) infection is a ma- jor cause of hepatocellular carcinoma (HCC). Circulating cell-free DNA (cfDNA) methylation of tumor suppressor genes are emerging potential biomarkers in HCC. We aimed to evaluate the cfDNA methylation status of RASSF1 and CDKN2AIP genes in patients with liver cirrhosis (LC) with or without HCC caused by HBV. Materials and Methods: A total of 47 patients with HBV cirrhosis were included in the study. Patients were divided into two groups: HCC and LC (HCC+LC, n=22) and HBV cirrhosis only (LC, n=25). cfDNA was iso- lated from the plasma samples of the patients. Methylation analysis was performed for RASSF1 and CDKN2AIP genes. Results: Mean methylation percentage of CDKN2AIP gene was 0.001±0.004% in the HCC+LC group and 0.008±0.004 % in the LC only group. The mean methylation percentage of RASSF1 gene was 5.1±16.1% in the HCC+LC group and 9.7±25.9% in the LC only group. The methylation rate of CDKN2AIP was significantly lower in the HCC+LC group (p=0.027). A positive correlation was found with the absence of cfDNA methylation of CDKN2AIP gene in the presence of HCC (R=0.667, p=0.018). Conclusion: cfDNA methylation of CDKN2AIP and RASSF1 genes may provide important diagnostic information regarding the development of HCC in the setting of HBV cirrhosis.

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1. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epi- demiology, etiology, and carcinogenesis. J Carcinog 2017;16:1.
2. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604.
3. Fung J, Lai CL, Yuen MF. Hepatitis B and C virus-related carcinogenesis. Clin Microbiol Infect 2009;15(11):964-970.
4. Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT, Sanderson SO, et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9(1):64-70.
5. Tatematsu K, Tanaka Y, Kurbanov F, Sugauchi F, Mano S, Maeshiro T, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype. J Virol 2009;83(20):10538-10547.
6. Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, et al. Re- sponse to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 2005;54(7):1009-1013.
7. Sonneveld MJ, Rijckborst V, Cakaloglu Y, Simon K, Heathcote EJ, Tabak F, et al. Durable hepatitis B surface antigen decline in hepatitis B e antigen- positive chronic hepatitis B patients treated with pegylated interferon-α2b: relation to response and HBV genotype. Antivir Ther 2012;17(1):9-17.
8. Akyuz F, Ciftci S, Keskin F, Cakiris A, Pinarbasi B, Baran B, et al. Ultra- deep pyrosequencing of precore/core promoter mutations in patients with genotype d chronic hepatitis B. J Gastroenterol Hepatol Res 2014;3(4):1030- 1034.
9. Leblebicioglu H, Eroglu C; Members of the Hepatitis Study Group. Acute hepatitis B virus infection in Turkey: epidemiology and genotype distribu- tion. Clin Microbiol Infect 2004;10(6):537-541.
10. Yalcin K, Degertekin H, Bahcecioglu IH, Demir A, Aladag M, Yildirim B, et al. Hepatitis B virus genotype D prevails in patients with persistently elevated or normal ALT levels in Turkey. Infection. 2004 Feb;32(1):24-29.
11. Harris PS, Hansen RM, Gray ME, Massoud OI, McGuire BM, Shoreibah MG. Hepatocellular carcinoma surveillance: An evidence-based approach. World J Gastroenterol 2019;25(13):1550-1559.
12. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and preven- tion of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018;68(3):526-549.
13. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocel- lular carcinoma in patients with cirrhosis: A meta-analysis. Gastroenterol- ogy 2018;154(6):1706-1718.e1.
14. Parikh ND, Mehta AS, Singal AG, Block T, Marrero JA, Lok AS. Biomark- ers for the Early Detection of Hepatocellular Carcinoma. Cancer Epidemiol Biomarkers Prev 2020;29(12):2495-2503.
15. Pezzuto F, Buonaguro L, Buonaguro FM, Tornesello ML. The Role of Cir- culating Free DNA and MicroRNA in Non-Invasive Diagnosis of HBV- and HCV-Related Hepatocellular Carcinoma. Int J Mol Sci 2018;19(4):1007.
16. Butt AN, Swaminathan R. Overview of circulating nucleic acids in plasma/ serum. Ann N Y Acad Sci 2008;1137:236-242.
17. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsy- chopharmacology 2013;38(1):23-38.
18. Lv X, Ye G, Zhang X, Huang T. p16 Methylation was associated with the de- velopment, age, hepatic viruses infection of hepatocellular carcinoma, and p16 expression had a poor survival: A systematic meta-analysis (PRISMA). Medicine (Baltimore) 2017;96(38):e8106.
19. Mocan T, Simão AL, Castro RE, Rodrigues CMP, Słomka A, Wang B, et al. Liquid biopsies in hepatocellular carcinoma: are we winning? J Clin Med 2020;9(5):1541.
20. Barták BK, Kalmár A, Galamb O, Wichmann B, Nagy ZB, Tulassay Z, et al. Blood collection and cell-free DNA Isolation methods influence the sensi- tivity of liquid biopsy analysis for colorectal cancer detection. Pathol Oncol Res 2019;25(3):915-923.
21. Gyanchandani R, Kvam E, Heller R, Finehout E, Smith N, Kota K, et al. Whole genome amplification of cell-free DNA enables detection of circu- lating tumor DNA mutations from fingerstick capillary blood. Sci Rep 2018 Nov 23;8(1):17313.
22. Llovet JM, Fuster J, Bruix J; Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular car- cinoma. Liver Transpl 2004;10(2 Suppl 1):S115-S120.
23. Volik S, Alcaide M, Morin RD, Collins C. Cell-free DNA (cfDNA): Clini- cal significance and utility in cancer shaped by emerging technologies. Mol Cancer Res 2016;14(10):898-908.
24. Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer- -a survey. Biochim Biophys Acta 2007;1775(1):181-232.
25. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomark- ers in cancer patients. Nat Rev Cancer 2011;11(6):426-437.
26. Breitbach S, Tug S, Simon P. Circulating cell-free DNA: an up-coming molecular marker in exercise physiology. Sports Med 2012;42(7):565-586.
27. Choy MK, Movassagh M, Goh HG, Bennett MR, Down TA, Foo RS. Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated. BMC Genomics 2010;11:519.
28. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986;321(6067):209-213.
29. Gibney ER, Nolan CM. Epigenetics and gene expression. Heredity (Edinb) 2010;105(1):4-13.
30. White GP, Watt PM, Holt BJ, Holt PG. Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differ- ences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells. J Immunol 2002;168(6):2820-2827.
31. Vivekanandan P, Thomas D, Torbenson M. Hepatitis B viral DNA is methy- lated in liver tissues. J Viral Hepat 2008;15(2):103-107.
32. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009;51(3):581-592.
33. Zhang Y, Li C, Zhang Y, Zhu H, Kang Y, Liu H, et al. Comparative analysis of CpG islands among HBV genotypes. PLoS One 2013;8(2):e56711.
34. Guo Y, Li Y, Mu S, Zhang J, Yan Z. Evidence that methylation of hepatitis B virus covalently closed circular DNA in liver tissues of patients with chronic hepatitis B modulates HBV replication. J Med Virol 2009;81(7):1177-1183.
35. Kim JW, Lee SH, Park YS, Hwang JH, Jeong SH, Kim N, et al. Replica- tive activity of hepatitis B virus is negatively associated with methylation of covalently closed circular DNA in advanced hepatitis B virus infection. Intervirology 2011;54(6):316-325.
36. Kaur P, Paliwal A, Durantel D, Hainaut P, Scoazec JY, Zoulim F, et al. DNA methylation of hepatitis B virus (HBV) genome associated with the devel- opment of hepatocellular carcinoma and occult HBV infection. J Infect Dis 2010;202(5):700-704.
37. Chotiyaputta W, Lok AS. Hepatitis B virus variants. Nat Rev Gastroenterol Hepatol 2009;6(8):453-462.
38. García-Gutiérrez L, McKenna S, Kolch W, Matallanas D. RASSF1A tu- mour suppressor: target the network for effective cancer therapy. Cancers (Basel) 2020;12(1):229.
39. Miki TS, Richter H, Rüegger S, Großhans H. PAXT-1 promotes XRN2 activity by stabilizing it through a conserved domain. Mol Cell 2014;53(2):351-360.
40. Tannapfel A, Busse C, Weinans L, Benicke M, Katalinic A, Geissler F, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene. 2001;20(48):7104-7109.
41. Nishida N, Goel A. Genetic and epigenetic signatures in human hepatocel- lular carcinoma: a systematic review. Curr Genomics 2011;12(2):130-137.
42. Zang JJ, Xie F, Xu JF, Qin YY, Shen RX, Yang JM, et al. P16 gene hyper- methylation and hepatocellular carcinoma: a systematic review and meta- analysis. World J Gastroenterol 2011;17(25):3043-3048.
43. Zhou Y, Wang XB, Qiu XP, Zhang S, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: A meta-analysis. Clin Res Hepatol Gastroenterol 2018;42(6):529-541.

APA	Telli P, Ozturk N, Hakan M, Çavuş B, Ormeci A, YAKUT A, Senkal I, Imanov Z, poyanli a, ISIK E, Demir K, Beşışık F, Kaymakoglu S, Yaylim I, Akyuz F (2022). Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. , 77 - 81. 10.14744/hf.2022.2022.0021
Chicago	Telli Pelin,Ozturk Nazli Begum,Hakan Mehmet Tolgahan,Çavuş Bilger,Ormeci Asli,YAKUT AYSUN,Senkal Ibrahim volkan,Imanov Ziya,poyanli arzu,ISIK EMINE GOKNUR,Demir Kadir,Beşışık Fatih,Kaymakoglu Sabahattin,Yaylim Ilhan,Akyuz Filiz Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. (2022): 77 - 81. 10.14744/hf.2022.2022.0021
MLA	Telli Pelin,Ozturk Nazli Begum,Hakan Mehmet Tolgahan,Çavuş Bilger,Ormeci Asli,YAKUT AYSUN,Senkal Ibrahim volkan,Imanov Ziya,poyanli arzu,ISIK EMINE GOKNUR,Demir Kadir,Beşışık Fatih,Kaymakoglu Sabahattin,Yaylim Ilhan,Akyuz Filiz Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. , 2022, ss.77 - 81. 10.14744/hf.2022.2022.0021
AMA	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. . 2022; 77 - 81. 10.14744/hf.2022.2022.0021
Vancouver	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. . 2022; 77 - 81. 10.14744/hf.2022.2022.0021
IEEE	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F "Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis." , ss.77 - 81, 2022. 10.14744/hf.2022.2022.0021
ISNAD	Telli, Pelin vd. "Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis". (2022), 77-81. https://doi.org/10.14744/hf.2022.2022.0021

APA	Telli P, Ozturk N, Hakan M, Çavuş B, Ormeci A, YAKUT A, Senkal I, Imanov Z, poyanli a, ISIK E, Demir K, Beşışık F, Kaymakoglu S, Yaylim I, Akyuz F (2022). Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. Hepatology forum, 3(3), 77 - 81. 10.14744/hf.2022.2022.0021
Chicago	Telli Pelin,Ozturk Nazli Begum,Hakan Mehmet Tolgahan,Çavuş Bilger,Ormeci Asli,YAKUT AYSUN,Senkal Ibrahim volkan,Imanov Ziya,poyanli arzu,ISIK EMINE GOKNUR,Demir Kadir,Beşışık Fatih,Kaymakoglu Sabahattin,Yaylim Ilhan,Akyuz Filiz Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. Hepatology forum 3, no.3 (2022): 77 - 81. 10.14744/hf.2022.2022.0021
MLA	Telli Pelin,Ozturk Nazli Begum,Hakan Mehmet Tolgahan,Çavuş Bilger,Ormeci Asli,YAKUT AYSUN,Senkal Ibrahim volkan,Imanov Ziya,poyanli arzu,ISIK EMINE GOKNUR,Demir Kadir,Beşışık Fatih,Kaymakoglu Sabahattin,Yaylim Ilhan,Akyuz Filiz Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. Hepatology forum, vol.3, no.3, 2022, ss.77 - 81. 10.14744/hf.2022.2022.0021
AMA	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. Hepatology forum. 2022; 3(3): 77 - 81. 10.14744/hf.2022.2022.0021
Vancouver	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis. Hepatology forum. 2022; 3(3): 77 - 81. 10.14744/hf.2022.2022.0021
IEEE	Telli P,Ozturk N,Hakan M,Çavuş B,Ormeci A,YAKUT A,Senkal I,Imanov Z,poyanli a,ISIK E,Demir K,Beşışık F,Kaymakoglu S,Yaylim I,Akyuz F "Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis." Hepatology forum, 3, ss.77 - 81, 2022. 10.14744/hf.2022.2022.0021
ISNAD	Telli, Pelin vd. "Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis". Hepatology forum 3/3 (2022), 77-81. https://doi.org/10.14744/hf.2022.2022.0021