Abstract
Purpose
Interleukin-10 (IL-10) is an immunoregulatory cytokine and its cervical and serum concentrations have been associated with a poor prognosis of cervical cancer. The rs1800872 polymorphism (c.-592C>A) in the promotor region of the IL-10 gene affects the production and expression of IL-10 and thus is able to determine the immune response profile in the cervix. Therefore, the aim of this work is to state the association between IL-10 c.-592C>A polymorphism and cervical cancer.
Methods
Genomic DNA was extracted from patient’s peripheral blood and tumor biopsy. Socio-demographic, sexual behavior and reproductive characteristics data were collected using a questionnaire.
Results
Co-dominant model in logistic binary regression adjusted for confounders, showed that patients presenting with C/A genotype had 2.15 times more chances for developing cervical cancer (OR 2.15; CI95% 1.02–4.56). The dominant model, C/A + A/A, was also independently associated with 2.71 times more chances for cervical cancer development when compared to control patients (OR 2.71; CI95% 1.05–4.47).
Conclusion
Our study analyses show the association between cervical cancer and IL-10 c.-592C>A polymorphism, demonstrating that the allele A presence was independently associated with higher risks of cervical cancer development.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and material
The data stated in this article including genotyping, sociodemographic profile, reproductive characteristics and sexual behavior are confidential. Medical record was analyzed under the permission of Londrina Cancer Hospital’s medical board direction. Data are available at the Laboratory of Molecular Genetics and Immunology supervised by Dra. Karen Brajão de Oliveira (Londrina, PR, Brazil; karen.brajao@uel.br), for researchers who meet the criteria to access confidential data. All information that support our findings are included within this article.
References
Appleby P, Beral V, Berrington De González A et al (2006) Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 118:1481–1495. https://doi.org/10.1002/ijc.21493
Bai CY, Shi XY, He J et al (2016) Association between IL-10 genetic variations and cervical cancer susceptibility in a Chinese population. Genet Mol Res 15:2–7. https://doi.org/10.4238/gmr.15038116
Barbisan G, Pérez LO, Contreras A, Golijow CD (2012) TNF-α and IL-10 promoter polymorphisms, HPV infection, and cervical cancer risk. Tumor Biol 33:1549–1556. https://doi.org/10.1007/s13277-012-0408-1
Bauer HM, Ting Y, Greer CE et al (1991) Genital human papillomavirus infection in female university students as determined by a PCR-based method. JAMA 265:472–477. https://doi.org/10.1001/jama.1991.03460040048027
Bermudez-Morales VH, Gutierrez LX, Alcocer-Gonzalez JM, Burguete A, Madrid-Marina V (2008) Correlation between IL-10 gene expression and HPV infection in cervical cancer: a mechanism for immune response escape. Cancer Invest 26(10):1037–1043. https://doi.org/10.1080/07357900802112693
Berti FCB, Pereira APL, Trugilo KP et al (2017) IL-10 gene polymorphism c.-592C%3eA increases HPV infection susceptibility and influences IL-10 levels in HPV infected women. Infect Genet Evol 53:128–134. https://doi.org/10.1016/j.meegid.2017.05.020
Bhairavabhotla RK, Verm V, Tongaonkar H et al (2007) Role of IL-10 in immune suppression in cervical cancer. Indian J Biochem Biophys 44:350–356
Capasso M, Avvisati RA, Piscopo C et al (2007) Cytokine gene polymorphisms in Italian preterm infants: association between interleukin-10–1082 G/A polymorphism and respiratory distress syndrome. Pediatr Res 61:313–317. https://doi.org/10.1203/pdr.0b013e318030d108
Chagas BS, Gurgel APAD, da Cruz HLA et al (2013) 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 19:32–37. https://doi.org/10.1016/j.meegid.2013.06.016
Cope A, Le Friec G, Cardone J, Kemper C (2011) The Th1 life cycle: molecular control of IFN-γ to IL-10 switching. Trends Immunol 32:278–286. https://doi.org/10.1016/j.it.2011.03.010
da Silva MC, Martins HPR, de Souza JL et al (2012) Prevalence of HPV infection and genotypes in women with normal cervical cytology in the state of Paraná, Brazil. Arch Gynecol Obstet 286:1015–1022. https://doi.org/10.1007/s00404-012-2399-y
Du GH, Wang JK, Richards JR, Wang JJ (2019) Genetic polymorphisms in tumor necrosis factor alpha and interleukin-10 are associated with an increased risk of cervical cancer. Int Immunopharmacol 66:154–161. https://doi.org/10.1016/j.intimp.2018.11.015
Eldridge RC, Pawlita M, Wilson L et al (2017) Smoking and subsequent human papillomavirus infection: a mediation analysis. Ann Epidemiol 27:724–730.e1. https://doi.org/10.1016/j.annepidem.2017.10.004
Guan P, Howell-Jones R, Li N et al (2012) Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer 131:2349–2359. https://doi.org/10.1002/ijc.27485
Hobbs K, Negri J, Klinnert M et al (1998) Interleukin-10 and transforming growth factor-β promoter polymorphisms in allergies and asthma. Am J Respir Crit Care Med 158:1958–1962. https://doi.org/10.1164/ajrccm.158.6.9804011
INCA - Instituto Nacional de Câncer José Alencar Gomes da Silva (2016) Diretrizes Brasileiras para o Rastreamento de Câncer de Colo de Útero. Ministério da Saúde, 2nd edn. Rio de Janeiro, RJ
Insinga RP, Perez G, Wheeler CM et al (2011) Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance. Cancer Epidemiol Biomark Prev 20:287–296. https://doi.org/10.1158/1055-9965.EPI-10-0791
Ivansson EL, Gustavsson IM, Magnusson JJ et al (2007) Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. Int J Cancer 121:2451–2457. https://doi.org/10.1002/ijc.22989
Kessler TA (2017) Cervical cancer: prevention and early detection. Semin Oncol Nurs 33:172–183. https://doi.org/10.1016/j.soncn.2017.02.005
Kubo M, Motomura Y (2012) Transcriptional regulation of the anti-inflammatory cytokine IL-10 in acquired immune cells. Front Immunol 3:1–9. https://doi.org/10.3389/fimmu.2012.00275
Lees BF, Erickson BK, Huh WK (2016) Cervical cancer screening: evidence behind the guidelines. Am J Obstet Gynecol 214:438–443. https://doi.org/10.1016/j.ajog.2015.10.147
Mannino MH, Zhu Z, Xiao H et al (2015) The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 367:103–107. https://doi.org/10.1016/j.canlet.2015.07.009
Mesri EA, Feitelson MA, Munger K (2014) Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15:266–282. https://doi.org/10.1016/j.chom.2014.02.011
Min Z, Pu X, Gu Z (2018) Correlative analysis of the expression of IL-10 and Ki-67 in human cervical cancer and cervical intraepithelial neoplasias and human papillomavirus infection. Oncol Lett 16:7189–7194. https://doi.org/10.3892/ol.2018.9520
Muñoz JP, Carrillo-Beltrán D, Aedo-Aguilera V et al (2018) Tobacco exposure enhances human papillomavirus 16 oncogene expression via EGFR/PI3K/Akt/c-Jun signaling pathway in cervical cancer cells. Front Microbiol 9:1–12. https://doi.org/10.3389/fmicb.2018.03022
Pestka S, Krause CD, Sarkar D et al (2004) Interleukine-10 and related cytokines and receptors. Annu Rev Immunol 22:929–979. https://doi.org/10.1146/annurev.immunol.22.012703.104622
Reeves G, Sweetland S, Kjaer S et al (2006) Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 119:1108–1124. https://doi.org/10.1002/ijc.21953
Rodriguez AC, Schiffman M, Herrero R et al (2008) Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. JNCI J Natl Cancer Inst 100:513–517. https://doi.org/10.1093/jnci/djn044
Roh JW, Kim MH, Seo SS et al (2002) Interleukin-10 promoter polymorphisms and cervical cancer risk in Korean women. Cancer Lett 184:57–63. https://doi.org/10.1016/S0304-3835(02)00193-3
Samir R, Asplund A, Tot T et al (2010) Tissue tumor marker expression in smokers, including serum cotinine concentrations, in women with cervical intraepithelial neoplasia or normal squamous cervical epithelium. Am J Obstet Gynecol 202:579.e1–579.e7. https://doi.org/10.1016/j.ajog.2009.11.034
Sasagawa T, Takagi H, Makinoda S (2012) Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. J Infect Chemother 18:807–815
Schiffman M, Castle PEC, Jeronimo J et al (2007) Human papillomavirus and cervical cancer. Lancet 56370:890–970. https://doi.org/10.2222/jsv.56.219
Simen-Kapeu A, Kataja V, Yliskoski M et al (2008) Smoking impairs human papillomavirus (HPV) type 16 and 18 capsids antibody response following natural HPV infection. Scand J Infect Dis 40:745–751. https://doi.org/10.1080/00365540801995360
Singhal P, Kumar A, Bharadwaj S et al (2015) Association of IL-10 GTC haplotype with serum level and HPV infection in the development of cervical carcinoma. Tumor Biol 36:2287–2298. https://doi.org/10.1007/s13277-014-2836-6
Steinke JW, Barekzi E, Hagman J, Borish L (2004) Functional analysis of −571 IL-10 promoter polymorphism reveals a repressor element controlled by Sp1. J Immunol 173:3215–3222. https://doi.org/10.4049/jimmunol.173.5.3215
Steinke JW, Barekzi E, Hagman J, Borish L (2014) Functional analysis of −571 IL-10 promoter polymorphism reveals a repressor element controlled by Sp1. J Immunol 173:3215–3222. https://doi.org/10.4049/jimmunol.173.5.3215
Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. https://doi.org/10.3322/caac.21262
Torres-Poveda K, Burguete-Garcia AI, Cruz M et al (2012) 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 7:32. https://doi.org/10.1186/1750-9378-7-32
Torres-Poveda K, Bahena-Román M, Madrid-González C et al (2014) Role of IL-10 and TGF-β1 in local immunosuppression in HPV-associated cervical neoplasia. World J Clin Oncol 5:753–763. https://doi.org/10.5306/wjco.v5.i4.753
Turner DM, Williams DM, Sankaran D et al (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8. https://doi.org/10.1111/j.1365-2370.1997.tb00001.x
Wheeler CM, Hunt WC, Joste NE et al (2009) Human Papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. JNCI J Natl Cancer Inst 101:475–487. https://doi.org/10.1093/jnci/djn510
WHO - World Health Organization (2016) UN Joint Global Programme on Cervical Cancer Prevention and Control
Zaid A, Hodny Z, Li R, Nelson BD (2001) Sp1 acts as a repressor of the human adenine nucleotide translocase-2 (ANT2) promoter. Eur J Biochem 268:5497–5503. https://doi.org/10.1046/j.1432-1033.2001.02453.x
Zidi S, Gazouani E, Stayoussef M et al (2015) IL-10 gene promoter and intron polymorphisms as genetic biomarkers of cervical cancer susceptibility among Tunisians. Cytokine 76:343–347. https://doi.org/10.1016/j.cyto.2015.05.028
Zoodsma M, Nolte IM, Schipper M et al (2005) Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease. Int J Gynecol Cancer 15:282–290. https://doi.org/10.1111/j.1525-1438.2005.00433.x
zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350. https://doi.org/10.1038/nrc798
Acknowledgements
The authors would like to acknowledge all the partnerships, and all patients that engaged voluntarily, who made this study possible. The Cancer Hospital of Londrina and the Molecular Immunopathology Laboratory in the Federal University of Paraná for granting the samples and Justiniano Clímaco da Silva’s Basic Health-care Unit for allowing our laboratory members to accompany the gynecology exams.
Funding
This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (470137/2013- 4), Fundação Araucária—Programa Pesquisa para o SUS (34935.406.36850.19112012). This work received fellowship support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior— Finance code 01.
Author information
Authors and Affiliations
Contributions
The study was designed by KBO. Data survey and sample collection were conducted by AP, KT, NO and MS. JDC-F analyzed all cancer biopsy. AP carried-out all the experiments regarding IL-10 genotyping. AP and KT performed biostatistical analysis. This manuscript was written and reviewed by AP, MAW and KBO.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethics approval
Institutional Ethics Committee Involving Humans of the State University of Londrina (Londrina, PR, Brazil) ratified this study (CEP/UEL 133/2012; CAAE 05505912.0.0000.523). All subjects signed an Informed Consent Form to participate and the study was conducted in accordance to the Helsinki’s Declaration.
Consent to participate
All subjects signed an informed consent form to participate and the study was conducted in accordance to the Helsinki’s Declaration.
Consent for publication
All subjects signed an informed consent form that consents publication of the data.
Code availability
All data generated or analysed during this study are included in this published article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Pereira, A.P.L., Trugilo, K.P., Okuyama, N.C.M. et al. IL-10 c.-592C>A (rs1800872) polymorphism is associated with cervical cancer. J Cancer Res Clin Oncol 146, 1971–1978 (2020). https://doi.org/10.1007/s00432-020-03256-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-020-03256-0