Tumor Biology

, Volume 33, Issue 5, pp 1549–1556 | Cite as

TNF-α and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk

  • Gisela Barbisan
  • Luis Orlando Pérez
  • Anahí Contreras
  • Carlos Daniel Golijow
Research Article


Although the implication of genetic factors in cervical cancer development remains to be elucidated, accumulative epidemiological evidence suggests that polymorphisms of cytokine genes may be involved in the etiology of cervical carcinoma. Tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) are two multifunctional cytokines implicated in inflammation, immunity, and cellular organization, and were proposed to play important roles in cancer biology. In order to determine whether IL-10 -1082 (G/A) and TNF-α -238 (G/A) and -308 (G/A) polymorphisms are associated with susceptibility to cervical cancer, a case–control study of 122 cancer patients and 176 healthy controls was conducted. Cervical samples were genotyped for both TNF-α polymorphisms by PCR-RFLP assay. SNP-1082 from IL-10 gene was genotyped using pyrosequencing technology. The association between cervical cancer risk and the studied SNPs was evaluated by logistic regression. Under univariate analysis, none of these polymorphisms appeared associated with susceptibility of cervical cancer development or HPV infection. However, individuals carrying heterozygous genotype for TNF-α -238 polymorphism seem to be at lower risk for cervical cancer development, with borderline significance (OR = 0.42, P = 0.069), as well as those carrying heterozygous genotypes for IL-10 and TNF-α -238 (OR = 0.40, P = 0.08). In conclusion, these results suggest a potential effect of TNF-α -238 G/A in the reduction of cervical cancer risk in Argentine women, but not TNF-α -308 or IL-10. Larger studies are needed to fully understand the genetic predisposition for the development of cervical cancer.


Cervical cancer IL-10 TNF-α Polymorphisms HPV 


Conflicts of interest



  1. 1.
    Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F. WHO International Agency for Research on Cancer (2005). Carcinogenicity of human papillomaviruses. Lancet Oncol. 2005;6:204.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  3. 3.
    Muñoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Hemminki K, Dong C, Vaittinen P. Familial risks in cervical cancer: is there a hereditary component? Int J Cancer. 1999;82:775–81.CrossRefPubMedGoogle Scholar
  5. 5.
    Horng JT, Hu KC, Wu LC, et al. Identifying the combination of genetic factors that determine susceptibility to cervical cancer. IEEE Trans Inf Technol Biomed. 2004;8:59–66.CrossRefPubMedGoogle Scholar
  6. 6.
    zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Kadish AS, Ho GY, Burk RD, et al. Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: outcome of HPV infection and associated neoplasia. J Natl Cancer Inst. 1997;89:1285–93.CrossRefPubMedGoogle Scholar
  8. 8.
    Clerici M, Merola M, Ferrario E, et al. Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection. J Natl Cancer Inst. 1997;89:245–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Tartour E, Gey A, Sastsre-Garou X, Lombard Surin I, Mosseri V, Fridman WH. Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. J Natl Cancer Inst. 1998;90:287–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Tartour E, Pannetier C, Mathiot C, et al. Prognostic value of cytokine and Fc gamma receptor assays in oncology. Immunol Lett. 1995;44:145–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;38:423–8.CrossRefGoogle Scholar
  12. 12.
    Li H, Groop L, Nilsson A, Weng J, Tuomi T. A combination of human leukocyte antigen DQB1*02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes. J Clin Endocr Metab. 2003;88:2767–74.CrossRefPubMedGoogle Scholar
  13. 13.
    Pillai S, Bikle DD, Eessalu TE, Aggarwal BB, Elias PM. Binding and biological effects of tumor necrosis factor alpha on cultured human neonatal foreskin keratinocytes. J Clin Invest. 1989;83:816–21.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Eksteen JA, Scott PA, Perry I, Jankowski JA. Inflammation promotes Barretts metaplasia and cancer: a unique role for TNF alpha. Eur J Cancer Prev. 2001;10:163–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997;34:391–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Wilson AG, Symons JA, McDowell TL, McDevitt HQ, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA. 1997;94:3195–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Höhler T, Kruger A, Gerken G, Schneider PM, Meyer zum Büschenfelde KH, Rittner C. Tumor necrosis factor alpha promoter polymorphism at position -238 is associated with chronic active hepatitis C infection. J Med Virol. 1998;54:173–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Jang WH, Yang YI, Yea SS, et al. The -238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers. Cancer Lett. 2001;166:41–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Strieter RM, Kunkel SL, Bone RC. Role of tumor necrosis factor-alpha in disease states and inflammation. Crit Care Med. 1993;21:S447–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Ardizzoia A, Lissoni P, Brivio F, et al. Tumor necrosis factor in solid tumors: increased blood levels in the metastasic disease. J Biol Regul Homeost Agents. 1992;6:103–7.PubMedGoogle Scholar
  21. 21.
    Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997;24:1–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Alamartine E, Berthoux P, Mariat C, Cambazard F, Berthoux F. Interleukin-10 promoter polymorphisms and susceptibility to skin squamous cell carcinoma after renal transplantation. J Invest Derm. 2003;120:99–103.CrossRefPubMedGoogle Scholar
  23. 23.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ting Y, Manos MM. Detection and typing of genital human Papillomavirus. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ, editors. PCR protocols. San Diego: Academic Pres; 1990. p. 356.Google Scholar
  25. 25.
    Evander M, Edlund K, Bodun E, et al. Comparison of a one-step and two-step polimerase chain reaction with degenerate general primers in a population-based study of human papillomavirus infection in young Swedish women. J Clin Microbiol. 1992;30:987–92.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Söderlund-Strand A, Rymark P, Andersson P, Dillner J, Dillner L. Comparison between the Hybrid Capture II Test and a PCR-Based Human Papillomavirus detection method for diagnosis and posttreatment follow-up of cervical intraepithelial neoplasia. J Clin Microbiol. 2005;43:3260–6.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Stanczuk GA, Sibanda EN, Perrey C, et al. Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production. Int J Cancer. 2001;94:792–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Deshpande A, Nolan JP, White PS, et al. TNF-alpha promoter polymorphisms and susceptibility to human papillomavirus 16-associated cervical cancer. J Infect Dis. 2005;191:969–76.CrossRefPubMedGoogle Scholar
  29. 29.
    Kirkpatrick A, Bidwell J, van den Brule AJ, Meijer CJ, Pawade J, Glew S. TNF alpha polymorphism frequencies in HPV-associated cervical dysplasia. Gynecol Oncol. 2004;92:675–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu L, Yang X, Chen X, et al. Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis. Mol Biol Rep. 2012;39:2683–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Badano I, Stietz SM, Schurr TG, et al. Analysis of TNF-α promoter SNPs and the risk of cervical cancer in urban populations of Posadas (Misiones, Argentina). J Clin Virol. 2012;53:54–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Govan VA, Constant D, Hoffman M, Williamson AL. The allelic distribution of -308 tumor necrosis factor-alpha gene polymorphism in South African women with cervical cancer and control women. BMC Cancer. 2006;6:24.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Stanczuk GA, Sibanda EN, Tswana SA, Bergstrom S. Polymorphism at the -308-promoter position of the tumor necrosis factor-alpha (TNF-alpha) gene and cervical cancer. Int J Gynecol Cancer. 2003;13:148–53.CrossRefPubMedGoogle Scholar
  34. 34.
    Ivansson EL, Juko-Pecirep I, Gyllensten UB. Interaction of immunological genes on chromosome 2q33 and IFNG in susceptibility to cervical cancer. Gynecol Oncol. 2010;116:544–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Calhoun ES, McGovern RM, Janney CA, et al. Host genetic polymorphism analysis in cervical cancer. Clin Chem. 2002;48:1218–24.PubMedGoogle Scholar
  36. 36.
    Magalhães RF, Biral AC, Pancoto JA, et al. Human leukocyte antigen (HLA) and single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-alpha -238 and -308 as genetic markers of susceptibility to psoriasis and severity of the disease in a long-term follow-up Brazilian study. Int J Dermatol. 2010;49:1133–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Nedoszytko B, Szczerkowska-Dobosz A, Zabłotna M, Gleń J, Rebała K, Roszkiewicz J. Associations of promoter region polymorphisms in the tumour necrosis factor-alpha gene and early-onset psoriasis vulgaris in a northern Polish population. Br J Dermatol. 2007;157:165–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Gostout BS, Poland GA, Calhoun ES, et al. TAP1, TAP2, and HLA-DR2 alleles are predictors of cervical cancer risk. Gynecol Oncol. 2003;88:326–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Fong CL, Siddiqui AH, Mark DF. Identification and characterization of a novel repressor site in the human tumor necrosis factor alpha gene. Nucleic Acids Res. 1994;22:1108–14.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    kaluza W, Reuss E, Grossmann S, et al. Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol. 2000;114:1180–3.CrossRefPubMedGoogle Scholar
  41. 41.
    Matsumoto K, Oki A, Satoh T, et al. Interleukin-10–1082 gene polymorphism and susceptibility to cervical cancer among Japanese women. Jpn J Clin Oncol. 2010;40:1113–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Zoodsma M, Nolte IM, Schipper M, et al. Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease. Int J Gynecol Cancer. 2005;15:282–90.CrossRefPubMedGoogle Scholar
  43. 43.
    Govan VA, Carrara HR, Sachs JA, Hoffman M, Stanczuk GA, Williamson AL. Ethnic differences in allelic distribution of IFN-g in South African women but no link with cervical cancer. J Carcinog. 2003;2:3.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Szöke K, Szalmás A, Szládek G, et al. IL-10 promoter nt -1082A/G polymorphism and human papillomavirus infection in cytologic abnormalities of the uterine cervix. J Interferon Cytokine Res. 2004;24:245–51.CrossRefPubMedGoogle Scholar
  45. 45.
    Reynard MP, Turner D, Navarrete CV. Allele frequencies of polymorphisms of the tumour necrosis factor-alpha, interleukin-10, interferon-gamma and interleukin-2 genes in a North European Caucasoid group from the UK. Eur J Immunogenet. 2000;27:241–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Perrey C, Pravica V, Sinnott PJ, Hutchinson IV. Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol. 1998;6:193–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum. 1998;41:1090–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Poli F, Nocco A, Berra S, et al. Allele frequencies of polymorphisms of TNFA, IL-6, IL-10 and IFNG in an Italian Caucasian population. Eur J Immunogenet. 2002;29:237–40.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Gisela Barbisan
    • 1
  • Luis Orlando Pérez
    • 1
  • Anahí Contreras
    • 1
  • Carlos Daniel Golijow
    • 1
  1. 1.IGEVET (Instituto de Genética Veterinaria “Ingeniero Fernando Noel Dulout”), Facultad de Ciencias VeterinariasUniversidad Nacional de La PlataBuenos AiresArgentina

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