Tumor Biology

, Volume 36, Issue 4, pp 2287–2298 | Cite as

Association of IL-10 GTC haplotype with serum level and HPV infection in the development of cervical carcinoma

  • Pallavi Singhal
  • Anoop Kumar
  • Soham Bharadwaj
  • Showket Hussain
  • Mausumi Bharadwaj
Research Article



Cervical cancer is the most common gynecological malignancy in the developing countries like India. In addition to human papillomavirus (HPV) infection, host genetic factors play an important role in viral persistence and neoplastic growth. IL-10, a multifunctional cytokine, plays an active role to promote tumor growth in the presence of HPV. The present study aims to find out the impact of IL-10 promoter polymorphisms at -1082A/G (rs1800896), -819C/T (rs1800872), and -592C/A (rs1800871) sites along with IL-10 production and HPV infection in the progression of cervical cancer.


We have genotyped a total of 506 subjects, 256 cases (208 cervical cancer + 48 precancer), and 250 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method followed by sequencing. IL-10 serum concentration was measured by enzyme-linked immunosorbent assay.


The frequency of IL-10 -592 variant genotype (AA) was found significantly reduced in cases as compare to controls while -1082 variant genotype (GG) was found ~4-fold higher risk of cervical cancer (p = <0.0001, OR = 3.667, 95 % CI = 2.329–5.773). On construction of haplotypes, GTC haplotype was emerged as a major risk haplotype while ACA haplotype was seemed as a marker for precancerous lesions. IL-10 serum concentration was observed higher in HPV-infected precancer and cancer cases. GTC haplotype was found to be coupled with higher serum concentration of IL-10 and HPV infection.


IL-10 polymorphisms play a role in cervical cancer development and that GTC haplotype, which is closely related to its serum concentration, maybe a useful biomarker for HPV-mediated cervical cancer.


Cervical cancer Human papillomavirus (HPV) Cytokines 



We would like to thank Dr. Sudha Salhan, Department of Obstetrics and Gynaecology, Safdarjung Hospital, New Delhi and Dr. Swaraj Batra, Department of Obstetrics and Gynaecology, LNJP Hospital, New Delhi, India for providing clinical samples and valuable feedback for the manuscript. We also would like to thank Dr. Suresh Bhambhani, Division of Cytopathology for pathological analysis of the clinical sample. We would like to thank the patients and their family members too. We would like to thank Dr. Dwaipayan Bharadwaj, CSIR-IGIB, New Delhi for critical evaluation of the manuscript. This work was supported by the core funding of ICPO (ICMR) to MB. PS is grateful to the Indian Council of Medical Research (ICMR), and AK is grateful to the University Grant commission (UGC) for their Senior Research Fellowships.

Conflicts of interest



  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11; 2013.Google Scholar
  2. 2.
    Kohaar I, Hussain S, Thakur N, Tiwari P, Nasare V, Batra S, et al. Association between human leukocyte antigen class II alleles and human papillomavirus-mediated cervical cancer in Indian women. Hum Immunol. 2009;70:222–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Zur HH. Papillomavirus infections—a major cause of human cancers. Biochim Biophys Acta. 1996;1288:F55–78.Google Scholar
  4. 4.
    Wu TC. Immunology of the human papilloma virus in relation to cancer. Curr Opin Immunol. 1994;6:746–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Wu TC, Kurman RJ. Analysis of cytokine profiles in patients with human papillomavirus-associated neoplasms. J Natl Cancer Inst. 1997;89:185–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Clerici M, Shearer GM, Clerici E. Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias: time to consider the TH1/TH2 paradigm. J Natl Cancer Inst. 1998;90:261–3.CrossRefPubMedGoogle Scholar
  7. 7.
    Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics. 1997;46:120–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM. The dual role of IL-10. Trends Immunol. 2003;24:36–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Woodworth CD, Lichti U, Simpson S, Evans CH, DiPaolo JA. Leukoregulin and gamma-interferon inhibit human papillomavirus type 16 gene transcription in human papillomavirus-immortalized human cervical cells. Cancer Res. 1992;52:456–63.PubMedGoogle Scholar
  10. 10.
    Madrigal M, Janicek MF, Sevin BU, Perras J, Estape R, Penalver M, et al. In vitro antigene therapy targeting HPV-16 E6 and E7 in cervical carcinoma. Gynecol Oncol. 1997;64:18–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Vairaktaris E, Yapijakis C, Serefoglou Z, Derka S, Vassiliou S, Nkenke E, et al. The interleukin-10 (-1082A/G) polymorphism is strongly associated with increased risk for oral squamous cell carcinoma. Anticancer Res. 2008;28:309–14.PubMedGoogle Scholar
  12. 12.
    Burada F, Dumitrescu T, Nicoli R, Ciurea ME, Rogoveanu I, Ioana M. Cytokine promoter polymorphisms and risk of colorectal cancer. Clin Lab. 2013;59:773–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu P, Song J, Su H, Li L, Lu N, Yang R, et al. IL-10 gene polymorphisms and susceptibility to systemic lupus erythematosus: a meta-analysis. PLoS One. 2013;8:e69547.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tsai CW, Tsai MH, Shih LC, Chang WS, Lin CC, Bau DT. Association of interleukin-10 (IL10) promoter genotypes with nasopharyngeal carcinoma risk in Taiwan. Anticancer Res. 2013;33:3391–6.PubMedGoogle Scholar
  15. 15.
    Wu Z, Zheng W, Xu J, Sun F, Chen H, Li P, Chen S, Shen M, Zhang W, You X, Wu Q, Zhang F, Li Y: IL10 polymorphisms associated with Behcet's disease in Chinese Han. Hum Immunol 2013.Google Scholar
  16. 16.
    Zheng XY, Guan WJ, Mao C, Chen HF, Ding H, Zheng JP, et al. Interleukin-10 promoter 1082/-819/-592 polymorphisms are associated with asthma susceptibility in Asians and atopic asthma: a meta-analysis. Lung. 2014;192:65–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Zou L, Wang L, Gong X, Zhao H, Jiang A, Zheng S: The association between three promoter polymorphisms of IL-10 and inflammatory bowel diseases (IBD): A meta-analysis. Autoimmunity 2013.Google Scholar
  18. 18.
    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
  19. 19.
    Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet. 1997;349:170–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239:487–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Sambrook Ra: Molecular Cloninig: A laboratory manual.; Cold Spring Harbor Laboratory Press 3, 2001.Google Scholar
  22. 22.
    Manos MM, Ting Y, Wright DK, Lewis AJ, Broker TR, Wolinski SM. Use of polymerase chain reaction amplification for the detection of genital human papillomaviruses. Cancer Cells. 1989;7:pp 209–14.Google Scholar
  23. 23.
    Roh JW, Kim MH, Seo SS, Kim SH, Kim JW, Park NH, et al. Interleukin-10 promoter polymorphisms and cervical cancer risk in Korean women. Cancer Lett. 2002;184:57–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Shekari M, Kordi-Tamandani DM, MalekZadeh K, Sobti RC, Karimi S, Suri V. Effect of anti-inflammatory (IL-4, IL-10) cytokine genes in relation to risk of cervical carcinoma. Am J Clin Oncol. 2012;35:514–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Zoodsma M, Nolte IM, Schipper M, Oosterom E, van der Steege G, de Vries EG, et al. Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease. Int J Gynecol Cancer. 2005;15 Suppl 3:282–90.CrossRefPubMedGoogle Scholar
  26. 26.
    Ivansson EL, Gustavsson IM, Magnusson JJ, Steiner LL, Magnusson PK, Erlich HA, et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. Int J Cancer. 2007;121:2451–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Singh H, Jain M, Sachan R, Mittal B. Association of TNFA (-308G > A) and IL-10 (-819C > T) promoter polymorphisms with risk of cervical cancer. Int J Gynecol Cancer. 2009;19:1190–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Matsumoto K, Oki A, Satoh T, Okada S, Minaguchi T, Onuki M, 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
  29. 29.
    Barbisan G, Perez LO, Contreras A, Golijow CD. TNF-alpha and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk. Tumour Biol. 2012;33:1549–56.CrossRefPubMedGoogle Scholar
  30. 30.
    Ni J, Ye Y, Teng F, Wu Q. Interleukin 10 polymorphisms and cervical cancer risk: a meta-analysis. Int J Gynecol Cancer. 2013;23:126–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Wang Q, Zhang C, Walayat S, Chen HW, Wang Y. Association between cytokine gene polymorphisms and cervical cancer in a Chinese population. Eur J Obstet Gynecol Reprod Biol. 2011;158:330–3.CrossRefPubMedGoogle Scholar
  32. 32.
    Chagas BS, Gurgel AP, da Cruz HL, Amaral CM, Cardoso MV, Silva Neto JC, et al. An interleukin-10 gene polymorphism associated with the development of cervical lesions in women infected with Human Papillomavirus and using oral contraceptives. Infect Genet Evol. 2013;19:32–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Liu J, Song B, Bai X, Liu W, Li Z, Wang J, et al. Association of genetic polymorphisms in the interleukin-10 promoter with risk of prostate cancer in Chinese. BMC Cancer. 2010;10:456.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wei YS, Kuang XH, Zhu YH, Liang WB, Yang ZH, Tai SH, et al. Interleukin-10 gene promoter polymorphisms and the risk of nasopharyngeal carcinoma. Tissue Antigens. 2007;70:12–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Yao JG, Gao LB, Liu YG, Li J, Pang GF. Genetic variation in interleukin-10 gene and risk of oral cancer. Clin Chim Acta. 2008;388:84–8.CrossRefPubMedGoogle Scholar
  36. 36.
    de Gruijl TD, Bontkes HJ, van den Muysenberg AJ, van Oostveen JW, Stukart MJ, van Verheijen RH, et al. Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix. Eur J Cancer. 1999;35:490–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Giannini SL, Al-Saleh W, Piron H, Jacobs N, Doyen J, Boniver J, et al. Cytokine expression in squamous intraepithelial lesions of the uterine cervix: implications for the generation of local immunosuppression. Clin Exp Immunol. 1998;113:183–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Torres-Poveda K, Burguete-Garcia AI, Cruz M, Martinez-Nava GA, Bahena-Roman M, Ortiz-Flores E, et al. The SNP at -592 of human IL-10 gene is associated with serum IL-10 levels and increased risk for human papillomavirus cervical lesion development. Infect Agent Cancer. 2012;7:32.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Stanczuk GA, Sibanda EN, Perrey C, Chirara M, Pravica V, Hutchinson IV, 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

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Pallavi Singhal
    • 1
  • Anoop Kumar
    • 1
  • Soham Bharadwaj
    • 2
  • Showket Hussain
    • 1
  • Mausumi Bharadwaj
    • 1
  1. 1.Division of Molecular Genetics and BiochemistryInstitute of Cytology and Preventive Oncology (ICMR)NoidaIndia
  2. 2.Department of BiotechnologyGuru Gobind Singh Indraprastha UniversityDwarkaIndia

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