Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Polymorphisms in Toll-like receptor genes and risk of cancer

Abstract

Host genetic factors are emerging as key determinants of disease risk for many cancers. Identifying candidate genes is a major challenge that has to stem from a profound understanding of the pathophysiology of the disease. The Toll-like receptors are important members of the host's innate immune response and their genes have been found to be polymorphic. This genetic variation allows for a more intricate repertoire that enables the host to withstand microbial challenges. While this may be advantageous on a population level, there may be less favourable outcomes for individuals that harbour certain genotypes associated with excessive immune activation and inflammatory drive. The damage is often collateral and is manifest in organs where this chronic inflammation alters normal physiology. A classic example of this paradigm is the Helicobacter pylori-induced gastric cancer model. Another emerging model is prostate cancer where Toll-like receptor polymorphisms have also been found to play a role. In this review, we discuss polymorphisms in Toll-like receptors and give an insight into how they may influence risk of cancer.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

References

  • Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M et al. (2000). TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25: 187–191.

    CAS  Article  PubMed  Google Scholar 

  • Backhed F, Rokbi B, Torstensson E, Zhao Y, Nilsson C, Seguin D et al. (2003). Gastric mucosal recognition of Helicobacter pylori is independent of Toll-like receptor 4. J Infect Dis 187: 829–836.

    Article  PubMed  Google Scholar 

  • Berghofer B, Frommer T, Konig IR, Ziegler A, Chakraborty T, Bein G et al. (2005). Common human Toll-like receptor 9 polymorphisms and haplotypes: association with atopy and functional relevance. Clin Exp Allergy 35: 1147–1154.

    CAS  Article  PubMed  Google Scholar 

  • Bochud PY, Hersberger M, Taffe P, Bochud M, Stein CM, Rodrigues SD et al. (2007). Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. Aids 21: 441–446.

    CAS  Article  PubMed  Google Scholar 

  • Collins FS, Green ED, Guttmacher AE, Guyer MS . (2003). A vision for the future of genomics research. Nature 422: 835–847.

    CAS  PubMed  Google Scholar 

  • De Marzo AM, Marchi VL, Epstein JI, Nelson WG . (1999). Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 155: 1985–1992.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • De Marzo AM, Meeker AK, Zha S, Luo J, Nakayama M, Platz EA et al. (2003). Human prostate cancer precursors and pathobiology. Urology 62: 55–62.

    Article  PubMed  Google Scholar 

  • De Marzo AM, Platz EA, Sutcliffe S, Xu JF, Gronberg H, Drake CG et al. (2007). Inflammation in prostate carcinogenesis. Nat Rev Cancer 7: 256–269.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Eder W, Klimecki W, Yu LZ, von Mutius E, Riedler J, Braun-Fahrlander C et al. (2004). Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113: 482–488.

    CAS  Article  PubMed  Google Scholar 

  • El-Omar EM . (2006). Role of host genes in sporadic gastric cancer. Best Pract Res Clin Gastroenterol 20: 675–686.

    CAS  Article  PubMed  Google Scholar 

  • El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA et al. (2000). Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404: 398–402.

    CAS  Article  PubMed  Google Scholar 

  • El-Omar EM, Oien K, El Nujumi A, Gillen D, Wirz A, Dahill S et al. (1997). Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology 113: 15–24.

    CAS  Article  PubMed  Google Scholar 

  • El-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE . (1995). Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 109: 681–691.

    CAS  Article  PubMed  Google Scholar 

  • El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB et al. (2003). Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124: 1193–1201.

    CAS  Article  PubMed  Google Scholar 

  • Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T et al. (2004). The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut 53: 987–992.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hamann L, Gomma A, Schroder NWJ, Stamme C, Glaeser C, Schulz S et al. (2005). A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J Mol Med 83: 478–485.

    CAS  Article  PubMed  Google Scholar 

  • Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH et al. (1996). The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 335: 242–249.

    CAS  Article  PubMed  Google Scholar 

  • Hawn TR, Misch EA, Dunstan SJ, Thwaites GE, Lans NTN, Quy HT et al. (2007). A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol 37: 2280–2289.

    CAS  Article  PubMed  Google Scholar 

  • Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ et al. (2003). A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J Exp Med 198: 1563–1572.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hawn TR, Wu H, Grossman JM, Hahn BH, Tsao BP, Aderem A . (2005). A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci USA 102: 10593–10597.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Higgins SC, Lavelle EC, McCann C, Keogh B, McNeela E, Byrne P et al. (2003). Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J Immunol 171: 3119–3127.

    CAS  Article  PubMed  Google Scholar 

  • Hold GL, Rabkin CS, Chow WH, Smith MG, Gammon MD, Risch HA et al. (2007). A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology 132: 905–912.

    CAS  Article  PubMed  Google Scholar 

  • Janeway Jr CA, Medzhitov R . (2002). Innate immune recognition. Annu Rev Immunol 20: 197–216.

    CAS  Article  PubMed  Google Scholar 

  • Jelavic TB, Barisic M, Hofman ID, Boraska V, Vrdoljak E, Peruzovic M et al. (2006). Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. Clin Genet 70: 156–160.

    Article  Google Scholar 

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). Cancer statistics, 2005. Ca Cancer J Clin 55: 10–30.

    Article  PubMed  Google Scholar 

  • Kang TJ, Chae GT . (2001). Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. Fems Immunol Med Microbiol 31: 53–58.

    CAS  Article  PubMed  Google Scholar 

  • Kawahara T, Kuwano Y, Teshima-Kondo S, Sugiyama T, Kawai T, Nikawa T et al. (2001a). Helicobacter pylori lipopolysaccharide from type I, but not type II strains, stimulates apoptosis of cultured gastric mucosal cells. J Med Invest 48: 167–174.

    CAS  PubMed  Google Scholar 

  • Kawahara T, Teshima S, Oka A, Sugiyama T, Kishi K, Rokutan K . (2001b). Type I Helicobacter pylori lipopolysaccharide stimulates toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cells. Infect Immun 69: 4382–4389.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E et al. (2002). Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347: 185–192.

    CAS  Article  PubMed  Google Scholar 

  • Kutukculer N, Yeniay BS, Aksu G, Berdeli A . (2007). Arg753Gln polymorphism of the human toll-like receptor-2 gene in children with recurrent febrile infections. Biochem Genet 45: 507–514.

    CAS  Article  PubMed  Google Scholar 

  • Lazarus R, Klimecki WT, Raby BA, Vercelli D, Palmer LJ, Kwiatkowski DJ et al. (2003). Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three US ethnic groups and exploratory case-control disease association studies. Genomics 81: 85–91.

    CAS  Article  PubMed  Google Scholar 

  • Lazarus R, Raby BA, Lange C, Silverman EK, Kwiatkowski DJ, Vercelli D et al. (2004). TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am J Respir Crit Care Med 170: 594–600.

    Article  PubMed  Google Scholar 

  • Lazarus R, Vercelli D, Palmer LJ, Klimecki WJ, Silverman EK, Richter B et al. (2002). Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease. Immunol Rev 190: 9–25.

    CAS  Article  PubMed  Google Scholar 

  • Lorenz E, Frees KL, Schwartz DA . (2001). Determination of the TLR4 genotype using allele-specific PCR. Biotechniques 31: 22–24.

    CAS  Article  PubMed  Google Scholar 

  • Lorenz E, Mira JP, Frees KL, Schwartz DA . (2002). Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162: 1028–1032.

    CAS  Article  PubMed  Google Scholar 

  • Macarthur M, Hold GL, El-Omar EM . (2004). Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am J Physiol Gastrointest Liver Physiol 286: G515–G520.

    CAS  Article  PubMed  Google Scholar 

  • Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S et al. (2003). A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125: 364–371.

    CAS  Article  PubMed  Google Scholar 

  • Mandell L, Moran AP, Cocchiarella A, Houghton J, Taylor N, Fox JG et al. (2004). Intact gram-negative Helicobacter pylori, Helicobacter felis, and Helicobacter hepaticus bacteria activate innate immunity via toll-like receptor 2 but not toll-like receptor 4. Infect Immun 72: 6446–6454.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR et al. (2006). Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci USA 103: 177–182.

    CAS  Article  PubMed  Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P . (2005). Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108.

    Article  PubMed  Google Scholar 

  • Pasare C, Medzhitov R . (2005). Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 560: 11–18.

    CAS  Article  PubMed  Google Scholar 

  • Peek Jr RM, Blaser MJ . (2002). Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer 2: 28–37.

    CAS  Article  PubMed  Google Scholar 

  • Pierik M, Joossens S, Van Steen K, Van Schuerbeek N, Vlietinck R, Rutgeerts P et al. (2006). Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis 12: 1–8.

    Article  PubMed  Google Scholar 

  • Pirie FJ, Pegoraro R, Motala AA, Rauff S, Rom L, Govender T et al. (2005). Toll-like receptor 3 gene polymorphisms in South African Blacks with type 1 diabetes. Tissue Antigens 66: 125–130.

    CAS  Article  PubMed  Google Scholar 

  • Risch NJ . (2000). Searching for genetic determinants in the new millennium. Nature 405: 847–856.

    CAS  Article  PubMed  Google Scholar 

  • Sanduleanu S, Jonkers D, De Bruine A, Hameeteman W, Stockbrugger RW . (2001). Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis. Aliment Pharmacol Ther 15: 1163–1175.

    CAS  Article  PubMed  Google Scholar 

  • Schmausser B, Andrulis M, Endrich S, Lee SK, Josenhans C, Muller-Hermelink HK et al. (2004). Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol 136: 521–526.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Schroder NW, Schumann RR . (2005). Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5: 156–164.

    Article  PubMed  Google Scholar 

  • Schroder NWJ, Hermann C, Hamann L, Gobel UB, Hartung T, Schumann RR . (2003). High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR. J Mol Med 81: 368–372.

    Article  PubMed  Google Scholar 

  • Segal ED, Lange C, Covacci A, Tompkins LS, Falkow S . (1997). Induction of host signal transduction pathways by Helicobacter pylori. Proc.. Proc Natl Acad Sci USA 94: 7595–7599.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Smith Jr MF, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K et al. (2003). Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem 278: 32552–32560.

    CAS  Article  PubMed  Google Scholar 

  • Su B, Ceponis PJ, Lebel S, Huynh H, Sherman PM . (2003). Helicobacter pylori activates Toll-like receptor 4 expression in gastrointestinal epithelial cells. Infect Immun 71: 3496–3502.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Suerbaum S, Michetti P . (2002). Helicobacter pylori infection. N Engl J Med 347: 1175–1186.

    CAS  Article  PubMed  Google Scholar 

  • Sun J, Wiklund F, Zheng SL, Chang B, Balter K, Li L et al. (2005). Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-1210912) and prostate cancer risk. J Natl Cancer Inst 97: 525–532.

    CAS  Article  PubMed  Google Scholar 

  • Takeda K, Akira S . (2005). Toll-like receptors in innate immunity. Int Immunol 17: 1–14.

    CAS  Article  PubMed  Google Scholar 

  • Tantisira K, Klimecki WT, Lazarus R, Palmer LJ, Raby BA, Kwiatkowski DJ et al. (2004). Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun 5: 343–346.

    CAS  Article  PubMed  Google Scholar 

  • Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP et al. (2004). Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5: 1166–1174.

    CAS  Article  PubMed  Google Scholar 

  • Yang IA, Barton SJ, Rorke S, Cakebread JA, Keith TP, Clough JB et al. (2004). Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun 5: 41–45.

    CAS  Article  PubMed  Google Scholar 

  • Zavros Y, Rieder G, Ferguson A, Samuelson LC, Merchant JL . (2002). Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology 122: 119–133.

    Article  PubMed  Google Scholar 

  • Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO et al. (2004). Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res 64: 2918–2922.

    CAS  Article  PubMed  Google Scholar 

  • Zhou XX, Jia WH, Shen GP, Qin HD, Yu XJ, Chen LZ et al. (2006). Sequence variants in toll-like receptor 10 are associated with nasopharyngeal carcinoma risk. Cancer Epidemiol Biomarkers Prev 15: 862–866.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E M El-Omar.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

El-Omar, E., Ng, M. & Hold, G. Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene 27, 244–252 (2008). https://doi.org/10.1038/sj.onc.1210912

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210912

Keywords

  • gastric cancer
  • Helicobacter pylori
  • genetic polymorphisms
  • single nucleotide polymorphisms
  • Toll-like receptors
  • prostate cancer

Further reading

Search

Quick links