Tumor Biology

, Volume 37, Issue 8, pp 10821–10826 | Cite as

Association of toll-like receptor 2 ∆22 and risk for gastric cancer considering main effects and interactions with smoking: a matched case-control study from Mizoram, India

  • Debdutta Mukherjee
  • Kangjam Rekha Devi
  • Manab Deka
  • Mridul Malakar
  • Tanvir Kaur
  • Debajit Barua
  • Jagadish Mahanta
  • Kanwar Narain
Original Article


Toll-like receptors (TLRs) are evolutionary conserved cell surface receptors of the innate immune system. Smoking has significant immunological effects which are mediated via TLRs on various receptor-mediated innate response pathways. Polymorphisms of TLR genes are associated with susceptibility toward various malignancies. The present study was undertaken to examine the association between TLR2 ∆22 and gastric cancer. In this study, we also investigated the interaction between TLR2 ∆22 and smoking. A total of 133 histologically confirmed gastric cancer cases and 266 age-sex-matched controls were selected for this study. TLR2 ∆22 genotypes were determined by allele-specific polymerase chain reaction (PCR). Binary conditional logistic regression analysis was used to find the association of TLR2 ∆22 with risk of gastric cancer. Logistic regression using hierarchically well-formulated models was used for interaction analysis between smoking and TLR2 ∆22. Persons having TLR2 ∆22 heterozygous genotype had two times increased risk of gastric cancer in multivariate logistic regression model. The interaction analysis using hierarchical logistic regression models between smoking and TLR2 ∆22 by calculating separate X 2 for interaction model and only main effect model, the difference of X 2 57.68−47.70 = 9.98 and degrees of freedom (df) 5−3 = 2, revealed significant (α = 0.05, df = 2) omnibus interaction. Our present study revealed TLR2 ∆22 to be significantly and independently associated with gastric cancer risk in Mizoram, and there is also evidence of significant interaction between smoking and TLR2 ∆22 with risk of gastric cancer.


TLR2 ∆22 Gastric cancer Logistic regression Smoking Interaction analysis 



This work was supported by the Indian Council of Medical Research (ICMR), India.

Compliance with ethical standards

The institutional ethical committee of the Regional Medical Research Centre, Dibrugarh, approved this study. All the subjects were explained about the nature of the study. All the subjects, both the cases, and the controls signed a written consent before donating blood for the study.

Conflicts of interest


Supplementary material

13277_2016_4982_MOESM1_ESM.docx (21 kb)
ESM 1 Table S1 Main effect between dummy variables of TLR2 (I/D + D/D) and alcohol drinking. Table S2Two-way interaction analysis between dummy variables of TLR2 (I/D + D/D) and alcohol drinking. Table S3 Main effect between dummy variables of TLR2 (I/D + D/D) and betel nut chewing. Table S4 Two-way interaction analysis between dummy variables of TLR2 (I/D + D/D) and betel nut chewing (DOCX 21 kb)
13277_2016_4982_MOESM2_ESM.docx (14 kb)
ESM 2 Table S5 Gastric cancer risk associated with combined uses of smoking, alcohol drinking, and betel nut chewing, Mizoram (DOCX 14 kb)


  1. 1.
    Qurieshi MA, Masoodi MA, Kadla SA, Ahmad SZ, Gangadharan P. Gastric cancer in Kashmir. Asian Pac J Cancer Prev. 2011;12(1):303–7.PubMedGoogle Scholar
  2. 2.
    Lu H, Ouyang W, Huang C. Inflammation, a key event in cancer development. Mol Cancer Res. 2006;4(4):221–33. doi: 10.1158/1541-7786.MCR-05-0261.CrossRefPubMedGoogle Scholar
  3. 3.
    Castano-Rodriguez N, Kaakoush NO, Mitchell HM. Pattern-recognition receptors and gastric cancer. Front Immunol. 2014;5:336. doi: 10.3389/fimmu.2014.00336.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kawai T, Akira S. Signaling to NF-kappaB by toll-like receptors. Trends Mol Med. 2007;13(11):460–9. doi: 10.1016/j.molmed.2007.09.002.CrossRefPubMedGoogle Scholar
  5. 5.
    Zeng HM, Pan KF, Zhang Y, Zhang L, Ma JL, Zhou T, et al. Genetic variants of toll-like receptor 2 and 5, Helicobacter pylori infection, and risk of gastric cancer and its precursors in a Chinese population. Cancer Epidemiol Biomark Prev. 2011;20(12):2594–602. doi: 10.1158/1055-9965.EPI-11-0702.CrossRefGoogle Scholar
  6. 6.
    El-Omar EM, Ng MT, Hold GL. Polymorphisms in toll-like receptor genes and risk of cancer. Oncogene. 2008;27(2):244–52. doi: 10.1038/sj.onc.1210912.CrossRefPubMedGoogle Scholar
  7. 7.
    de Oliveira JG, Silva AE. Polymorphisms of the TLR2 and TLR4 genes are associated with risk of gastric cancer in a Brazilian population. World J Gastroenterol. 2012;18(11):1235–42. doi: 10.3748/wjg.v18.i11.1235.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pandey S, Mittal RD, Srivastava M, Srivastava K, Singh S, Srivastava S, et al. Impact of toll-like receptors [TLR] 2 (−196 to −174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women. Gynecol Oncol. 2009;114(3):501–5. doi: 10.1016/j.ygyno.2009.05.032.CrossRefPubMedGoogle Scholar
  9. 9.
    Mandal RK, George GP, Mittal RD. Association of toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population. Mol Biol Rep. 2012;39(7):7263–9. doi: 10.1007/s11033-012-1556-5.CrossRefPubMedGoogle Scholar
  10. 10.
    Srivastava K, Srivastava A, Kumar A, Mittal B. Significant association between toll-like receptor gene polymorphisms and gallbladder cancer. Liver Int. 2010;30(7):1067–72. doi: 10.1111/j.1478-3231.2010.02268.x.CrossRefPubMedGoogle Scholar
  11. 11.
    Theodoropoulos GE, Saridakis V, Karantanos T, Michalopoulos NV, Zagouri F, Kontogianni P, et al. Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development. Breast. 2012;21(4):534–8. doi: 10.1016/j.breast.2012.04.001.CrossRefPubMedGoogle Scholar
  12. 12.
    Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, Sakata M, et al. Toll-like receptor 2–196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer. Cancer Sci. 2007;98(11):1790–4. doi: 10.1111/j.1349-7006.2007.00590.x.CrossRefPubMedGoogle Scholar
  13. 13.
    Malakar M, Devi KR, Phukan RK, Kaur T, Deka M, Puia L, et al. Genetic polymorphism of glutathione S-transferases M1 and T1, tobacco habits and risk of stomach cancer in Mizoram, India. Asian Pac J Cancer Prev. 2012;13(9):4725–32.CrossRefPubMedGoogle Scholar
  14. 14.
    Malakar M, Devi KR, Phukan RK, Kaur T, Deka M, Puia L, et al. CYP2E1 genetic polymorphism with dietary, tobacco, alcohol habits, H. pylori infection status and susceptibility to stomach cancer in Mizoram, India. Asian Pac J Cancer Prev. 2014;15(20):8815–22.CrossRefPubMedGoogle Scholar
  15. 15.
    Malakar M, Devi KR, Phukan RK, Kaur T, Deka M, Puia L, et al. p53 codon 72 polymorphism interactions with dietary and tobacco related habits and risk of stomach cancer in Mizoram, India. Asian Pac J Cancer Prev. 2014;15(2):717–23.CrossRefPubMedGoogle Scholar
  16. 16.
    Phukan RK, Narain K, Zomawia E, Hazarika NC, Mahanta J. Dietary habits and stomach cancer in Mizoram, India. J Gastroenterol. 2006;41(5):418–24. doi: 10.1007/s00535-006-1761-x.CrossRefPubMedGoogle Scholar
  17. 17.
    Phukan RK, Zomawia E, Narain K, Hazarika NC, Mahanta J. Tobacco use and stomach cancer in Mizoram, India. Cancer Epidemiol Biomark Prev. 2005;14(8):1892–6. doi: 10.1158/1055-9965.EPI-05-0074.CrossRefGoogle Scholar
  18. 18.
    Mehta H, Nazzal K, Sadikot RT. Cigarette smoking and innate immunity. Inflamm Res. 2008;57(11):497–503. doi: 10.1007/s00011-008-8078-6.CrossRefPubMedGoogle Scholar
  19. 19.
    Laan M, Bozinovski S, Anderson GP. Cigarette smoke inhibits lipopolysaccharide-induced production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. J Immunol. 2004;173(6):4164–70.CrossRefPubMedGoogle Scholar
  20. 20.
    Valacchi G, Pagnin E, Phung A, Nardini M, Schock BC, Cross CE, et al. Inhibition of NFkappaB activation and IL-8 expression in human bronchial epithelial cells by acrolein. Antioxid Redox Signal. 2005;7(1–2):25–31. doi: 10.1089/ars.2005.7.25.CrossRefPubMedGoogle Scholar
  21. 21.
    Droemann D, Goldmann T, Tiedje T, Zabel P, Dalhoff K, Schaaf B. Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients. Respir Res. 2005;6:68. doi: 10.1186/1465-9921-6-68.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, Sakata M, et al. Toll-like receptor 2 (TLR) -196 to 174del polymorphism in gastro-duodenal diseases in Japanese population. Dig Dis Sci. 2008;53(4):919–24. doi: 10.1007/s10620-007-9950-x.CrossRefPubMedGoogle Scholar
  23. 23.
    Kleinbaum DG, Klein M, Pryor ER. Logistic regression: a self-learning text. 3rd ed. Statistics in the health sciences. New York: Springer; 2010.CrossRefGoogle Scholar
  24. 24.
    Zhu L, Yuan H, Jiang T, Wang R, Ma H, Zhang S. Association of TLR2 and TLR4 polymorphisms with risk of cancer: a meta-analysis. PLoS One. 2013;8(12), e82858. doi: 10.1371/journal.pone.0082858.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chen H, Cowan MJ, Hasday JD, Vogel SN, Medvedev AE. Tobacco smoking inhibits expression of proinflammatory cytokines and activation of IL-1R-associated kinase, p38, and NF-kappaB in alveolar macrophages stimulated with TLR2 and TLR4 agonists. J Immunol. 2007;179(9):6097–106.CrossRefPubMedGoogle Scholar
  26. 26.
    Metcalfe HJ, Lea S, Hughes D, Khalaf R, Abbott-Banner K, Singh D. Effects of cigarette smoke on toll-like receptor (TLR) activation of chronic obstructive pulmonary disease (COPD) macrophages. Clin Exp Immunol. 2014;176(3):461–72. doi: 10.1111/cei.12289.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Semlali A, Witoled C, Alanazi M, Rouabhia M. Whole cigarette smoke increased the expression of TLRs, HBDs, and proinflammatory cytokines by human gingival epithelial cells through different signaling pathways. PLoS One. 2012;7(12), e52614. doi: 10.1371/journal.pone.0052614.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Noakes PS, Hale J, Thomas R, Lane C, Devadason SG, Prescott SL. Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses. Eur Respir J. 2006;28(4):721–9. doi: 10.1183/09031936.06.00050206.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Debdutta Mukherjee
    • 1
  • Kangjam Rekha Devi
    • 1
  • Manab Deka
    • 2
  • Mridul Malakar
    • 1
  • Tanvir Kaur
    • 3
  • Debajit Barua
    • 4
  • Jagadish Mahanta
    • 1
  • Kanwar Narain
    • 1
  1. 1.Regional Medical Research CentreN.E. Region (Indian Council of Medical Research)DibrugarhIndia
  2. 2.Department of Biological SciencesGauhati UniversityGuwahatiIndia
  3. 3.Indian Council of Medical ResearchNew DelhiIndia
  4. 4.Aizawl Endoscopy CentreAizawlIndia

Personalised recommendations