Tumor Biology

, Volume 35, Issue 2, pp 1495–1502 | Cite as

Quantitative assessment of the influence of tumor necrosis factor alpha polymorphism with gastritis and gastric cancer risk

  • Ming Li
  • Yinping Wang
  • Yahong Gu
Research Article


Tumor necrosis factor alpha (TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04–1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations.


TNFA Polymorphism Gastritis Gastric cancer Meta-analysis 


Conflicts of interest


Supplementary material

13277_2013_1206_MOESM1_ESM.docx (147 kb)
ESM 1 (DOCX 146 kb)


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Peek Jr RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28–37.PubMedCrossRefGoogle Scholar
  4. 4.
    El Omar EM, Chow WH, Rabkin CS. Gastric cancer and H. pylori: host genetics open the way. Gastroenterology. 2001;121:1002–4.PubMedGoogle Scholar
  5. 5.
    Macarthur M, Hold GL, El Omar EM. Inflammation and cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol. 2004;286:G515–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society Award lecture on cancer epidemiology and prevention. Cancer Res. 1992;52:6735–40.PubMedGoogle Scholar
  7. 7.
    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72:1605–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Raabe T, Bukrinsky M, Currie RA. Relative contribution of transcription and translation to the induction of tumor necrosis factor-alpha by lipopolysaccharide. J Biol Chem. 1998;273:974–80.PubMedCrossRefGoogle Scholar
  9. 9.
    Skoog T, van't Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, et al. A common functional polymorphism (C→A substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet. 1999;8:1443–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K, et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet. 1999;22:145–50.PubMedCrossRefGoogle Scholar
  11. 11.
    Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet. 1992;1:353.PubMedCrossRefGoogle Scholar
  12. 12.
    Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–9.PubMedCrossRefGoogle Scholar
  13. 13.
    McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994;371:508–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Cabrera M, Shaw MA, Sharples C, Williams H, Castes M, Convit J, et al. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med. 1995;182:1259–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Bernal W, Moloney M, Underhill J, Donaldson PT. Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis. J Hepatol. 1999;30:237–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Li DW, Collier DA, He L. Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. Hum Mol Genet. 2006;15:1995–2002.PubMedCrossRefGoogle Scholar
  17. 17.
    Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.CrossRefGoogle Scholar
  18. 18.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.PubMedCrossRefGoogle Scholar
  19. 19.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  20. 20.
    Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18:2693–708.PubMedCrossRefGoogle Scholar
  21. 21.
    Egger M, Davey Smith G, Schneider M. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCrossRefGoogle Scholar
  22. 22.
    Jang WH, Yang YI, Yea SS, Lee YJ, Chun JH, Kim HI, et al. The -238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers. Cancer Lett. 2001;166:41–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Yea SS, Yang YI, Jang WH, Lee YJ, Bae HS, Paik KH. Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection. J Clin Pathol. 2001;54:703–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Lanas A, García-González MA, Santolaria S, Crusius JB, Serrano MT, Benito R, et al. TNF and LTA gene polymorphisms reveal different risk in gastric and duodenal ulcer patients. Genes Immun. 2001;2:415–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, et al. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364–71.PubMedCrossRefGoogle Scholar
  26. 26.
    El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193–201.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee SG, Kim B, Yook JH, Oh ST, Lee I, Song K. TNF/LTA polymorphisms and risk for gastric cancer/duodenal ulcer in the Korean population. Cytokine. 2004;28:75–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Glas J, Török HP, Schneider A, Brünnler G, Kopp R, Albert ED, et al. Allele 2 of the interleukin-1 receptor antagonist gene is associated with early gastric cancer. J Clin Oncol. 2004;22:4746–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Fei BY, Xia B, Deng CS, Xia XQ, Xie M, Crusius JB, et al. Association of tumor necrosis factor genetic polymorphism with chronic atrophic gastritis and gastric adenocarcinoma in Chinese Han population. World J Gastroenterol. 2004;10:1256–61.PubMedGoogle Scholar
  30. 30.
    Perri F, Piepoli A, Bonvicini C, Gentile A, Quitadamo M, Di Candia M, et al. Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. Cytokine. 2005;30:293–302.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee JY, Kim HY, Kim KH, Kim SM, Jang MK, Park JY, et al. Association of polymorphism of IL-10 and TNF-A genes with gastric cancer in Korea. Cancer Lett. 2005;225:207–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Lu W, Pan K, Zhang L, Lin D, Miao X, You W. Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. Carcinogenesis. 2005;26:631–6. s.PubMedCrossRefGoogle Scholar
  33. 33.
    Li C, Xia B, Yang Y, Li J, Xia HH. TNF gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in Chinese population. Am J Gastroenterol. 2005;100:290–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Zambon CF, Basso D, Navaglia F, Belluco C, Falda A, Fogar P, et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine. 2005;29:141–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Rocha GA, Guerra JB, Rocha AM, Saraiva IE, da Silva DA, de Oliveira CA, et al. IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma. Int J Cancer. 2005;115:678–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Garza-González E, Bosques-Padilla FJ, El-Omar E, Hold G, Tijerina-Menchaca R, Maldonado-Garza HJ, et al. Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer. 2005;114:237–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Garcia-Gonzalez MA, Savelkoul PH, Benito R, Santolaria S, Crusius JB, Peña AS, et al. No allelic variant associations of the IL-1 and TNF gene polymorphisms in the susceptibility to duodenal ulcer disease. Int J Immunogenet. 2005;32:299–306.PubMedCrossRefGoogle Scholar
  38. 38.
    Lu CC, Sheu BS, Chen TW, Yang HB, Hung KH, Kao AW, et al. Host TNF-alpha-1031 and −863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection. Am J Gastroenterol. 2005;100:1274–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Morgan DR, Dominguez RL, Keku TO, Heidt PE, Martin CF, Galanko JA, et al. Gastric cancer and the high combination prevalence of host cytokine genotypes and Helicobacter pylori in Honduras. Clin Gastroenterol Hepatol. 2006;4:1103–11.PubMedCrossRefGoogle Scholar
  40. 40.
    Kim N, Cho SI, Yim JY, Kim JM, Lee DH, Park JH, et al. The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea. Helicobacter. 2006;11:105–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Kamangar F, Abnet CC, Hutchinson AA, Newschaffer CJ, Helzlsouer K, Shugart YY, et al. Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). Cancer Causes Control. 2006;17:117–25.PubMedCrossRefGoogle Scholar
  42. 42.
    Hou L, El-Omar EM, Chen J, Grillo P, Rabkin CS, Baccarelli A, et al. Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer. Carcinogenesis. 2007;28:118–23.PubMedCrossRefGoogle Scholar
  43. 43.
    Sugimoto M, Furuta T, Shirai N, Nakamura A, Xiao F, Kajimura M, et al. Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer. J Gastroenterol Hepatol. 2007;22:51–9.PubMedCrossRefGoogle Scholar
  44. 44.
    García-González MA, Lanas A, Quintero E, Nicolás D, Parra-Blanco A, Strunk M, et al. Gastric cancer susceptibility is not linked to pro-and anti-inflammatory cytokine gene polymorphisms in whites: a nationwide multicenter study in Spain. Am J Gastroenterol. 2007;102:1878–92.PubMedCrossRefGoogle Scholar
  45. 45.
    Crusius JB, Canzian F, Capellá G, Peña AS, Pera G, Sala N, et al. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST). Ann Oncol. 2008;19:1894–902.PubMedCrossRefGoogle Scholar
  46. 46.
    Achyut BR, Tripathi P, Ghoshal UC, Moorchung N, Mittal B. Interleukin-10 (-819 C/T) and tumor necrosis factor-alpha (-308 G/A) gene variants influence gastritis and lymphoid follicle development. Dig Dis Sci. 2008;53:622–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Chakravorty M, De Datta D, Choudhury A, Santra A, Roychoudhury S. Association of specific haplotype of TNFalpha with Helicobacter pylori-mediated duodenal ulcer in eastern Indian population. J Genet. 2008;87:299–304.PubMedCrossRefGoogle Scholar
  48. 48.
    Szoke D, Molnar B, Solymosi N, Klausz G, Gyulai Z, Toth B, et al. T-251A polymorphism of IL-8 relating to the development of histological gastritis and G-308A polymorphism of TNF-alpha relating to the development of macroscopic erosion. Eur J Gastroenterol Hepatol. 2008;20:191–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Murphy G, Thornton J, McManus R, Swan N, Ryan B, Hughes DJ, et al. Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4. Eur J Gastroenterol Hepatol. 2009;21:630–5.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Xiao H, Li C, Jiang Y, Li R, Xia B. The relationship among IL-10. TNF gene polymorphisms, Helicobacter pylori infection and gastroduodenal diseases in Hubei Han ethnic. Zhonghua Nei Ke Za Zhi. 2009;48:552–6.PubMedGoogle Scholar
  51. 51.
    Barbosa HPM, Martins LC, dos Santos SEB, Demachki S, Assumpção MB, Aragão CD, et al. Interleukin-1 and TNF-α polymorphisms and Helicobacter pylori in a Brazilian Amazon population. World J Gastroenterol. 2009;15:1465–71.CrossRefGoogle Scholar
  52. 52.
    Yang JJ, Ko KP, Cho LY, Shin A, Gwack J, Chang SH, et al. The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case–control study. BMC Cancer. 2009;9:238.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Cheng HH, Chang CS, Wang HJ, Wang WC. Interleukin-1beta and -10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients. J Gastroenterol Hepatol. 2010;25:1443–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Shin CM, Kim N, Lee HS, Lee DH, Kim JS, Jung HC, et al. Intrafamilial aggregation of gastric cancer: a comprehensive approach including environmental factors, Helicobacter pylori virulence, and genetic susceptibility. Eur J Gastroenterol Hepatol. 2011;23:411–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Santos JC, Ladeira MS, Pedrazzoli Jr J, Ribeiro ML. Relationship of IL-1 and TNF-α polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population. Braz J Med Biol Res. 2012;45:811–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Hong Y, Ge Z, Jing C, Shi J, Dong X, Zhou F, et al. Functional promoter -308G>A variant in tumor necrosis factor α gene is associated with risk and progression of gastric cancer in a Chinese population. PLoS One. 2013;8:e50856.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    de Oliveira JG, Rossi AF, Nizato DM, Miyasaki K, Silva AE. Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer. Dig Dis Sci. 2013;58:978–88.PubMedCrossRefGoogle Scholar
  58. 58.
    Han F, Wang X, Wang X, Luo Y, Li W. Meta-analysis of the association of CYP1A1 polymorphisms with gastric cancer susceptibility and interaction with tobacco smoking. Mol Biol Rep. 2012;39:8335–44.PubMedCrossRefGoogle Scholar
  59. 59.
    Kwon HJ, Won YS, Nam KT, Yoon YD, Jee H, Yoon WK, et al. Vitamin D3 upregulated protein 1 deficiency promotes N-methyl-N-nitrosourea and Helicobacter pylori-induced gastric carcinogenesis in mice. Gut. 2012;61:53–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histoclinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.PubMedGoogle Scholar
  61. 61.
    Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT, et al. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol. 2006;7:27–38.PubMedCrossRefGoogle Scholar
  62. 62.
    Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94:1680–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Beales IL, Calam J. Interleukin 1 beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways. Gut. 1998;42:227–34.PubMedCrossRefGoogle Scholar
  64. 64.
    Noach LA, Bosma NB, Jansen J, Hoek FJ, van Deventer SJ, Tytgat GN. Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J Gastroenterol. 1994;29:425–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–52.PubMedCrossRefGoogle Scholar
  66. 66.
    Neu B, Puschmann AJ, Mayerhofer A, Hutzler P, Grossmann J, Lippl F, et al. TNF-alpha induces apoptosis of parietal cells. Biochem Pharmacol. 2003;65:1755–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Abrahamsson J, Carlsson B, Mellander L. Tumor necrosis factor-alpha in malignant disease. J Pediatr Hematol Oncol. 1993;15:364–9.Google Scholar
  68. 68.
    Nakashima J, Tachibana M, Ueno M, Miyajima A, Baba S, Murai M. Association between tumor necrosis factor in serum and cachexia in patients with prostate cancer. Clin Cancer Res. 1998;4:1743–8.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of General Surgery, Qingpu Branch of Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of General Surgery, Ren Ji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China

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