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EGF rs4444903 polymorphism is associated with risk of HCV-related cirrhosis and HBV/HCV-related hepatocellular carcinoma

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Abstract

Objective

The epidermal growth factor (EGF) rs4444903 polymorphism is associated with aberrant expression of EGF, which was a characteristic of cirrhotic liver diseases, induces highly malignant hepatocellular carcinoma (HCC). Numerous studies have uncovered the association of this polymorphism with the risk of liver disease, but with inconsistent findings.

Materials and methods

Therefore, this meta-analysis was performed to evaluate whether EGF rs4444903 polymorphism conferred susceptibility to liver disease. Totally 18 eligible articles were identified by searching PubMed, Google, CNKI and EMBASE up to December 1, 2020.

Results

Our results indicated that there was no significant difference in the minor G allele frequency of rs4444903 polymorphism between HBV/HCV carriers and healthy controls. In other words, EGF rs4444903 polymorphism was not associated with the risk of HBV/HCV. Interestingly, this polymorphism increased the risk of liver cirrhosis in the controls with HCV infection. Additionally, EGF rs4444903 polymorphism is associated with the increased risk of HCC under the five models. Subgroup analysis by ethnicity shows that rs4444903 polymorphism intensifies the risk of HCC among Asians and Caucasians. Strong correlation is also reported in controls with cirrhosis or HCV infection and studies using PCR–RFLP genotyping.

Conclusions

The study supports that EGF rs4444903 polymorphism is a genetic contributor to liver cirrhosis and HCC in the overall population. Nevertheless, this conclusion must be confirmed by larger studies with more diverse ethnic populations.

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References

  1. Villanueva A (2019) Hepatocellular Carcinoma. N Engl J Med 380:1450–1462

    Article  CAS  PubMed  Google Scholar 

  2. Budny A, Kozłowski P, Kamińska M et al (2017) Epidemiology and risk factors of hepatocellular carcinoma. Pol Merkur Lekarski 43:133–139

    PubMed  Google Scholar 

  3. Xie M, Yang Z, Liu Y et al (2018) The role of HBV-induced autophagy in HBV replication and HBV related-HCC. Life Sci 205:107–112

    Article  CAS  PubMed  Google Scholar 

  4. Hajarizadeh B, Grebely J, Dore GJ (2013) Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 10:553–562

    Article  CAS  PubMed  Google Scholar 

  5. Lee SM, Kim-Ha J, Choi WY et al (2016) Interplay of genetic and epigenetic alterations in hepatocellular carcinoma. Epigenomics 8:993–1005

    Article  CAS  PubMed  Google Scholar 

  6. Zeng F, Harris RC (2014) Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol 28:2–11

    Article  CAS  PubMed  Google Scholar 

  7. Brenndörfer ED, Karthe J, Frelin L et al (2009) Nonstructural 3/4A protease of hepatitis C virus activates epithelial growth factor-induced signal transduction by cleavage of the T-cell protein tyrosine phosphatase. Hepatology 49:1810–1820

    Article  PubMed  Google Scholar 

  8. Iwamoto M, Saso W, Sugiyama R et al (2019) Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization. Proc Natl Acad Sci USA 116:8487–8492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gan CJ, Li WF, Li CN et al (2020) EGF receptor inhibitors comprehensively suppress hepatitis B virus by downregulation of STAT3 phosphorylation. Biochem Biophys Rep 22:100763

    PubMed  PubMed Central  Google Scholar 

  10. Kömüves LG, Feren A, Jones AL et al (2000) Expression of epidermal growth factor and its receptor in cirrhotic liver disease. J Histochem Cytochem 48:821–830

    Article  PubMed  Google Scholar 

  11. Yoneda N, Sato Y, Kitao A et al (2011) Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma. Lab Invest 91:262–272

    Article  CAS  PubMed  Google Scholar 

  12. Lake BM, Lawrence ND, Tenenbaum JB (2018) The emergence of organizing structure in conceptual representation. Cogn Sci 42(Suppl 3):809–832

    Article  PubMed  Google Scholar 

  13. Shahbazi M, Pravica V, Nasreen N et al (2002) Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397–401

    Article  CAS  PubMed  Google Scholar 

  14. Zhang S, Qiao K, Trieu C et al (2017) Genetic polymorphism of epidermal growth factor rs4444903 influences susceptibility to HCV-related liver cirrhosis and hepatocellular carcinoma in a chinese han population. Clin Lab 63:845–850

    CAS  PubMed  Google Scholar 

  15. Yuan JM, Fan Y, Ognjanovic S et al (2013) Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies. BMC Gastroenterol 13:32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu J, Zhang W, Xu A et al (2013) Association of epidermal growth factor and epidermal growth factor receptor polymorphisms with the risk of hepatitis B virus-related hepatocellular carcinoma in the population of North China. Genet Test Mol Biomarkers 17:595–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang H (2009) Epidemal growth factor gene polymorphisms associated with susceptibility to hepatocellular carcinoma. Guangxi Medical University.

  18. Tanabe KK, Lemoine A, Finkelstein DM et al (2008) Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA 299:53–60

    Article  CAS  PubMed  Google Scholar 

  19. Suenaga M, Yamada S, Fujii T et al (2013) A functional polymorphism in the epidermal growth factor gene predicts hepatocellular carcinoma risk in Japanese hepatitis C patients. Onco Targets Ther 6:1805–1812

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shi HZ, Ren P, Lu QJ et al (2012) Association between EGF, TGF-β1 and TNF-α gene polymorphisms and hepatocellular carcinoma. Asian Pac J Cancer Prev 13:6217–6220

    Article  PubMed  Google Scholar 

  21. Qi P, Wang H, Chen YM et al (2009) No association of EGF 5’UTR variant A61G and hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. Pathology 41:555–560

    Article  CAS  PubMed  Google Scholar 

  22. Li Y, Xie Q, Lu F et al (2010) Association between epidermal growth factor 61A/G polymorphism and hepatocellular carcinoma susceptibility in Chinese patients. Liver Int 30:112–118

    Article  CAS  PubMed  Google Scholar 

  23. Huang CF, Huang CY, Yeh ML et al (2017) Genetics variants and serum levels of mhc class I chain-related A in predicting hepatocellular carcinoma development in chronic hepatitis c patients post antiviral treatment. EBioMedicine 15:81–89

    Article  PubMed  Google Scholar 

  24. Gholizadeh M, Khosravi A, Torabian P et al (2017) Association of the epidermal growth factor gene +61A>G polymorphism with hepatocellular carcinoma in an Iranian population. Gastroenterol Hepatol Bed Bench 10:284–288

    PubMed  PubMed Central  Google Scholar 

  25. El-Bendary M, Neamatallah M, El-Maksoud MA et al (2013) 640 epidemal growth factor genetic polymorphism predicts risk of hepatocellular carcinoma in egyptian patients with HCV (genotype 4)-related cirrhosis. J Hepatol 58:S261–S261

    Article  Google Scholar 

  26. Chen K, Wei Y, Yang H et al (2011) Epidermal growth factor +61 G/A polymorphism and the risk of hepatocellular carcinoma in a Chinese population. Genet Test Mol Biomarkers 15:251–255

    Article  CAS  PubMed  Google Scholar 

  27. Baghdadi I, Abu Ella K, El Shaaraway A et al (2020) Genetic polymorphism of epidermal growth factor gene as a predictor of hepatocellular carcinoma in hepatitis C cirrhotic patients. Asian Pac J Cancer Prev 21:2047–2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Falleti E, Cmet S, Fabris C et al (2012) Association between the epidermal growth factor rs4444903 G/G genotype and advanced fibrosis at a young age in chronic hepatitis C. Cytokine 57:68–73

    Article  CAS  PubMed  Google Scholar 

  29. Cmet S, Fabris C, Fattovich G et al (2012) Carriage of the EGF rs4444903 A>G functional polymorphism associates with disease progression in chronic HBV infection. Clin Exp Immunol 167:296–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Abu Dayyeh BK, Yang M, Fuchs BC et al (2011) A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology 141:141–149

    Article  CAS  PubMed  Google Scholar 

  31. Abbas E, Shaker O, Abd El Aziz G et al (2012) Epidermal growth factor gene polymorphism 61A/G in patients with chronic liver disease for early detection of hepatocellular carcinoma: a pilot study. Eur J Gastroenterol Hepatol 24:458–463

    CAS  PubMed  Google Scholar 

  32. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605

    Article  PubMed  Google Scholar 

  33. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  34. Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang P, Xu X, Wang L et al (2014) The role of EGF-EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J Cell Mol Med 18:218–230

    Article  CAS  PubMed  Google Scholar 

  36. Tönjes RR, Löhler J, O’Sullivan JF et al (1995) Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene 10:765–768

    PubMed  Google Scholar 

  37. Okamoto K, Neureiter D, Alinger B et al (2008) The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice. Int J Oncol 33:733–742

    CAS  PubMed  Google Scholar 

  38. Zhu Y, Chen Z, Jiang H et al (2019) The genetic association between EGF A61G polymorphism (rs4444903) and risk of colorectal cancer: An update meta-analysis and trial sequential analysis. Medicine (Baltimore) 98:e14007

    Article  CAS  Google Scholar 

  39. Piao Y, Liu Z, Ding Z et al (2013) EGF +61A>G polymorphism and gastrointestinal cancer risk: a HuGE review and meta-analysis. Gene 519:26–33

    Article  CAS  PubMed  Google Scholar 

  40. Laus AC, de Paula FE, de Lima MA et al (2019) EGF+61 A>G polymorphism is not associated with lung cancer risk in the Brazilian population. Mol Biol Rep 46:2417–2425

    Article  CAS  PubMed  Google Scholar 

  41. Hu M, Shi H, Xu Z et al (2013) Association between epidermal growth factor gene rs4444903 polymorphism and risk of glioma. Tumour Biol 34:1879–1885

    Article  CAS  PubMed  Google Scholar 

  42. Yang Z, Wu Q, Shi Y et al (2012) Epidermal growth factor 61A>G polymorphism is associated with risk of hepatocellular carcinoma: a meta-analysis. Genet Test Mol Biomarkers 16:1086–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhong JH, You XM, Gong WF et al (2012) Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-analysis. PLoS ONE 7:e32159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun S, Jin GJ, Zhao Y et al (2015) Association between the epidermal growth factor 61*A/G polymorphism and hepatocellular carcinoma risk: a meta-analysis. Asian Pac J Cancer Prev 16:3009–3014

    Article  PubMed  Google Scholar 

  45. Shen XF, Zeng XT, Jian ZY et al (2015) Quantitative assessment of the effect of epidermal growth factor 61A/G polymorphism on the risk of hepatocellular carcinoma. Oncol Lett 10:3199–3205

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li YL, Tian Z, Zhao L et al (2014) Association between the EGF rs4444903 polymorphism and liver cancer susceptibility: a meta-analysis and meta-regression. Genet Mol Res 13:8066–8079

    Article  CAS  PubMed  Google Scholar 

  47. Jiang G, Yu K, Shao L et al (2015) Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies. BMC Cancer 15:314

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Correspondence to Guixia Meng.

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Wang, J., Zhong, Y. & Meng, G. EGF rs4444903 polymorphism is associated with risk of HCV-related cirrhosis and HBV/HCV-related hepatocellular carcinoma. Int J Clin Oncol 26, 2053–2064 (2021). https://doi.org/10.1007/s10147-021-01994-w

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