Tumor Necrosis Factor-α 238 G/A Polymorphism and Risk of Hepatocellular Carcinoma: Evidence from a Meta-analysis

  • Cheng, Ke (35 Ward of Transplantation, The Third Xiangya hospital of Central South University) ;
  • Zhao, Yu-Jun (35 Ward of Transplantation, The Third Xiangya hospital of Central South University) ;
  • Liu, Lian (35 Ward of Transplantation, The Third Xiangya hospital of Central South University) ;
  • Wan, Jing-Jing (Surgery center, The Third Xiangya hospital of Central South University)
  • Published : 2013.05.30


Background: Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) plays a very important role in the development and progression of cancer. Many epidemiological studies have evaluated associations between the TNF-${\alpha}$ 238 G/A polymorphism and hepatocellular carcinoma (HCC) risk, but the published data are inconclusive. Therefore, we performed the present meta-analysis. Methods: Electronic searches of several databases were conducted for all publications on the association between TNF-${\alpha}$ 238 G/A polymorphism and HCC through July 2012. Asummary odds ratio (OR) with its 95% confidence interval (CI) were calculated to evaluate the strength of this association. Results: Eleven case-control studies with a total of 1,572 HCC cases and 1,875 controls were finally included in this meta-analysis. Overall, the TNF-${\alpha}$ 238 G/A polymorphism was significantly associated with increased risk of hepatocellular carcinoma in three genetic comparison models (For A versus G: OR 1.32, 95%CI 1.04-1.69, P = 0.02, $I_2$ = 40%; for AG versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.03, $I_2$ = 40%; for AA/AG versus GG: OR 1.33, 95%CI 1.03-1.72, P = 0.03, $I_2$ = 41%) when all studies were pooled. Subgroup analysis by ethnicity further showed that there was a significant association between the TNF-${\alpha}$ 238 G/A polymorphism and risk of HCC in Asians under three genetic comparison models (For A versus G: OR 1.30, 95%CI 1.00-1.68, P = 0.05, $I_2$ = 45% for AA/AG versus GG: OR 1.31, 95%CI 1.00-1.71, P = 0.05, $I_2$ = 46%). Conclusions: This meta-analysis provided convincing evidence that the TNF-${\alpha}$ 238 G/A polymorphism is associated with increased susceptibility to HCC. However, more well-designed studies with large sample size are needed to validate this association in Caucasians.


Tumor necrosis factor-${\alpha}$;hepatocellular carcinoma;single nucleotide polymorphism;meta-analysis


  1. Aggarwal BB, Gupta SC, Kim JH (2012). Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood, 119, 651-65.
  2. Bridges JF, Joy SM, Gallego G, et al (2011). Needs for hepatocellular carcinoma control policy in the Asia-Pacific region. Asian Pac J Cancer Prev, 12, 2585-91.
  3. Chen X, Zhang L, Chang Y, et al (2011). Association of TNFalpha genetic polymorphisms with hepatocellular carcinoma susceptibility: a case-control study in a Han Chinese population. Int J Biol Markers, 26, 181-7.
  4. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  5. El-Serag HB (2011). Hepatocellular carcinoma. N Engl J Med, 365, 1118-27.
  6. Falvo JV, Tsytsykova AV, Goldfeld AE (2010). Transcriptional control of the TNF gene. Curr Dir Autoimmun, 11, 27-60.
  7. Fan W, Maoqing W, Wangyang C, et al (2011). Relationship between the polymorphism of tumor necrosis factoralpha-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: a meta-analysis. Eur J Hum Genet, 19, 432-7.
  8. Harkisoen S, Arends JE, van Erpecum KJ, et al (2012). Hepatitis B viral load and risk of HBV-related liver disease: from East to West? Ann Hepatol, 11, 164-71.
  9. Heneghan MA, Johnson PJ, Clare M, et al (2003). Frequency and nature of cytokine gene polymorphisms in hepatocellular carcinoma in Hong Kong Chinese. Int J Gastrointest Cancer, 34, 19-26.
  10. Higgins JP, Thompson SG, Deeks JJ, et al (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60.
  11. Huang HL, Xie JS, Huang ZS, et al (2007). The Relationship of Polymorphism of Tulnor Necrosis Factor-Ot Gene Promoter-238G/A with Prhnary Hepatic Carcinoma in Patients. Progress Anatomical Sci, 13, 11-3.
  12. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  13. Jeng JE, Tsai JF, Chuang LY, et al (2007). Tumor necrosis factoralpha 308.2 polymorphism is associated with advanced hepatic fibrosis and higher risk for hepatocellular carcinoma. Neoplasia, 9, 987-92.
  14. Jeng JE, Tsai HR, Chuang LY, et al (2009). Independent and additive interactive effects among tumor necrosis factoralpha polymorphisms, substance use habits, and chronic hepatitis B and hepatitis C virus infection on risk for hepatocellular carcinoma. Medicine (Baltimore), 88, 349-57.
  15. Jung KW, Ha E, Yu GI, et al (2009). TNFalpha promoter polymorphism is a risk factor for susceptibility in hepatocellular carcinoma in Korean population. Clin Chim Acta, 407, 16-9.
  16. Kummee P, Tangkijvanich P, Poovorawan Y, et al (2007). Association of HLA-DRB1*13 and TNF-alpha gene polymorphisms with clearance of chronic hepatitis B infection and risk of hepatocellular carcinoma in Thai population. J Viral Hepat, 14, 841-8.
  17. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  18. Marcos M, Gomez-Munuera M, Pastor I, et al (2009). Tumor necrosis factor polymorphisms and alcoholic liver disease: a HuGE review and meta-analysis. Am J Epidemiol, 170, 948-56.
  19. Mocellin S, Nitti D (2008). TNF and cancer: the two sides of the coin. Front Biosci, 13, 2774-83.
  20. Niro GA, Fontana R, Gioffreda D, et al (2005). Tumor necrosis factor gene polymorphisms and clearance or progression of hepatitis B virus infection. Liver Int, 25, 1175-81.
  21. Postal M, Appenzeller S (2011). The role of Tumor Necrosis Factor-alpha (TNF-alpha) in the pathogenesis of systemic lupus erythematosus. Cytokine, 56, 537-43.
  22. Qidwai T, Khan F (2011). Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol, 74, 522-47.
  23. Salanti G, Amountza G, Ntzani EE, et al (2005). Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet, 13, 840-8.
  24. Sethi G, Shanmugam MK, Ramachandran L, et al (2012). Multifaceted link between cancer and inflammation. Biosci Rep, 32, 1-15.
  25. Suganuma M, Watanabe T, Yamaguchi K, et al (2012). Human gastric cancer development with TNF-alpha-inducing protein secreted from Helicobacter pylori. Cancer Lett, 322, 133-8.
  26. Sun SC (2012). The noncanonical NF-kappaB pathway. Immunol Rev, 246, 125-40.
  27. Vujanovic NL (2011). Role of TNF superfamily ligands in innate immunity. Immunol Res, 50, 159-74.
  28. Walczak H (2011). TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol Rev, 244, 9-28.
  29. Wang B, Huang G, Wang D, et al (2010a). Null genotypes of GSTM1 and GSTT1 contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. J Hepatol, 53, 508-18.
  30. Wang B, Wang J, Zheng Y, et al (2010b). A study of TNFalpha-238 and -308 polymorphisms with different outcomes of persistent hepatitis B virus infection in China. Pathology, 42, 674-80.
  31. Wang CK, Zhang CY, Huang TR, et al (2012). Correlation between TNF-$\alpha$ polymorphisms and family clustering of primary liver cancer in Guangxi. Chin J of Oncol Prev and Treat, 4, 149-53.
  32. Wang J, Cao C, Luo H, et al (2011). Tumour necrosis factor alpha -308G/A polymorphism and risk of the four most frequent cancers: a meta-analysis. Int J Immunogenet, 38, 311-20.
  33. Wang Y, Kato N, Hoshida Y, et al (2003). Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology, 37, 65-71.
  34. Wiangnon S, Kamsa-ard S, Suwanrungruang K, et al (2012). Trends in incidence of hepatocellular carcinoma, 1990-2009, Khon Kaen, Thailand. Asian Pac J Cancer Prev, 13, 1065-8.
  35. Zhou P, Lv GQ, Wang JZ, et al (2011). The TNF-alpha-238 polymorphism and cancer risk: a meta-analysis. PLoS One, 6, e22092.

Cited by

  1. Association of Serum and Salivary Tumor Necrosis Factor-α with Histological Grading in Oral Cancer and its Role in Differentiating Premalignant and Malignant Oral Disease vol.15, pp.17, 2014,
  2. The association between the polymorphisms of TNF-α and non-Hodgkin lymphoma: a meta-analysis vol.35, pp.12, 2014,
  3. Independent and Additive Interaction Between Tumor Necrosis Factor β +252 Polymorphisms and Chronic Hepatitis B and C Virus Infection on Risk and Prognosis of Hepatocellular Carcinoma: a Case-Control Study vol.15, pp.23, 2015,
  4. Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma vol.95, pp.50, 2016,
  5. Tumor Necrosis Factor-α-308 G/A Polymorphisms and Risk of Hepatocellular Carcinoma: A Meta-Analysis vol.inpress, pp.inpress, 2016,