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Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women

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Abstract

Interleukin 6 (IL6) encodes a cytokine protein, which functions in inflammation, maintains immune homeostasis and plays important roles in cervical carcinogenesis. Single nucleotide polymorphisms (SNPs) in IL6 that cause variations in host immune response may contribute to cervical cancer risk. In this two-stage case–control study with a total of 1,584 cervical cancer cases and 1,768 cancer-free female controls, we investigated associations between two IL6 SNPs and cervical cancer risk in Eastern Chinese women. In both Study 1 and Study 2, we found a significant association of the IL6-rs2069837 SNP with an increased risk of cervical cancer as well as in their combined data (OR 1.27 and 1.19, 95 % CI 1.08–1.49 and 1.04–1.36, P = 0.004 and 0.014 for dominant and additive genetic models, respectively). Furthermore, rs2069837 variant AG/GG carriers showed significantly higher levels of IL6 protein than did rs2069837 AA carriers in the target tissues. Using multifactor dimensionality reduction (MDR) and classification and regression tree (CART) analyses, we observed some evidence of interactions of the IL6 rs2069837 SNP with age at primiparity and menopausal status in cervical cancer risk. We concluded that the IL6-rs2069837 SNP may be a marker for susceptibility to cervical cancer in Eastern Chinese women by a possible mechanism of altering the IL6 protein expression. Although lacked information on human papillomavirus (HPV) infection, our study also suggested possible interactions between IL6 genotypes and age at primiparity or menopausal status in cervical carcinogenesis. However, larger, independent studies with detailed HPV infection data are warranted to validate our findings.

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Abbreviations

HPV:

Human papillomavirus

IL6:

Interleukin 6

SNP:

Single nucleotide polymorphism

FUSCC:

Fudan University Shanghai Cancer Center

TZL:

Taizhou longitudinal study

BMI:

Body mass index

FIGO:

International Federation of Gynecology and Obstetrics

LN:

Lymph node

LVSI:

Lympho–vascular space invasion

ER:

Estrogen receptor

PR:

Progesterone receptor

UTR:

Untranslated region

MAF:

Minor allele frequency

LD:

Linkage disequilibrium

TFBS:

Transcription factor binding site

IHC:

Immunohistochemistry

MDR:

Multifactor dimensionality reduction

CART:

Classification and regression tree

OR:

Odds ratio

CI:

Confidence interval

FPRP:

False positive report probability

HWE:

Hardy–Weinberg equilibrium

CVC:

Cross-validation consistency

TN:

Terminal node

ChIP:

Chromatin immunoprecipitation

References

  • Abdelwahab SI, Abdul AB, Zain ZN, Hadi AH (2012) Zerumbone inhibits interleukin-6 and induces apoptosis and cell cycle arrest in ovarian and cervical cancer cells. Int Immunopharmacol 12:594–602

    Article  PubMed  CAS  Google Scholar 

  • Bedoya AM, Jaramillo R, Baena A, Castano J, Olaya N, Zea AH, Herrero R, Sanchez GI (2012) Location and density of immune cells in precursor lesions and cervical cancer. Cancer Microenviron. doi:10.1007/s12307-012-0097-8

    PubMed  Google Scholar 

  • Castro FA, Haimila K, Sareneva I, Schmitt M, Lorenzo J, Kunkel N, Kumar R, Forsti A, Kjellberg L, Hallmans G, Lehtinen M, Hemminki K, Pawlita M (2009) Association of HLA-DRB1, interleukin-6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population–a candidate gene approach. Int J Cancer 125:1851–1858

    Article  PubMed  CAS  Google Scholar 

  • Chen M, Kamat AM, Huang M, Grossman HB, Dinney CP, Lerner SP, Wu X, Gu J (2007) High-order interactions among genetic polymorphisms in nucleotide excision repair pathway genes and smoking in modulating bladder cancer risk. Carcinogenesis 28:2160–2165

    Article  PubMed  CAS  Google Scholar 

  • Cheng X, Yang G, Schmeler KM, Coleman RL, Tu X, Liu J, Kavanagh JJ (2011) Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy. Gynecol Oncol 121:323–327

    Article  PubMed  CAS  Google Scholar 

  • Combarros O, van Duijn CM, Hammond N, Belbin O, Arias-Vasquez A, Cortina-Borja M, Lehmann MG, Aulchenko YS, Schuur M, Kolsch H, Heun R, Wilcock GK, Brown K, Kehoe PG, Harrison R, Coto E, Alvarez V, Deloukas P, Mateo I, Gwilliam R, Morgan K, Warden DR, Smith AD, Lehmann DJ (2009) Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer’s disease. J Neuroinflamm 6:22

    Article  Google Scholar 

  • Galvan A, Ioannidis JP, Dragani TA (2010) Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends Genet 26:132–141

    Article  PubMed  CAS  Google Scholar 

  • Gangwar R, Mittal B, Mittal RD (2009) Association of interleukin-6 -174G>C promoter polymorphism with risk of cervical cancer. Int J Biol Markers 24:11–16

    PubMed  CAS  Google Scholar 

  • Gruol DL, Nelson TE (1997) Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol 15:307–339

    Article  PubMed  CAS  Google Scholar 

  • Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, Clifford GM (2012) Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer 131:2349–2359

    Google Scholar 

  • He BZ, Holloway AK, Maerkl SJ, Kreitman M (2011) Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules. PLoS Genet 7:e1002053

    Article  PubMed  CAS  Google Scholar 

  • He J, Qiu LX, Wang MY, Hua RX, Zhang RX, Yu HP, Wang YN, Sun MH, Zhou XY, Yang YJ, Wang JC, Jin L, Wei QY, Li J (2012) Polymorphisms in the XPG gene and risk of gastric cancer in Chinese populations. Hum Genet 131:1235–1244

    Article  PubMed  CAS  Google Scholar 

  • International Collaboration of Epidemiological Studies of Cervical Cancer (2007) Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 120:885–891

    Article  Google Scholar 

  • Iyori M, Zhang T, Pantel H, Gagne BA, Sentman CL (2011) TRAIL/DR5 plays a critical role in NK cell-mediated negative regulation of dendritic cell cross-priming of T cells. J Immunol 187:3087–3095

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  • Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-6 family of cytokines and gp130. Blood 86:1243–1254

    PubMed  CAS  Google Scholar 

  • Kwon EM, Salinas CA, Kolb S, Fu R, Feng Z, Stanford JL, Ostrander EA (2011) Genetic polymorphisms in inflammation pathway genes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 20:923–933

    Article  PubMed  CAS  Google Scholar 

  • Lim WY, Chen Y, Ali SM, Chuah KL, Eng P, Leong SS, Lim E, Lim TK, Ng AW, Poh WT, Tee A, Teh M, Salim A, Seow A (2011) Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers. Carcinogenesis 32:522–529

    Article  PubMed  CAS  Google Scholar 

  • Macintyre DA, Sykes L, Teoh TG, Bennett PR (2012) Prevention of preterm labour via the modulation of inflammatory pathways. J Matern Fetal Neonatal Med. doi:10.3109/14767058.2012.666114

  • MacQuarrie KL, Fong AP, Morse RH, Tapscott SJ (2011) Genome-wide transcription factor binding: beyond direct target regulation. Trends Genet 27:141–148

    Article  PubMed  CAS  Google Scholar 

  • Nogueira de Souza NC, Brenna SM, Campos F, Syrjanen KJ, Baracat EC, Silva ID (2006) Interleukin-6 polymorphisms and the risk of cervical cancer. Int J Gynecol Cancer 16:1278–1282

    Article  PubMed  CAS  Google Scholar 

  • Pecorelli S (2009) Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2:103–104

    Google Scholar 

  • Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69:138–147

    Article  PubMed  CAS  Google Scholar 

  • Sepkovic DW, Bradlow HL, Ho G, Hankinson SE, Gong L, Osborne MP, Fishman J (1995) Estrogen metabolite ratios and risk assessment of hormone-related cancers. Assay validation and prediction of cervical cancer risk. Ann NY Acad Sci 768:312–316

    Article  PubMed  CAS  Google Scholar 

  • Therneau TM, Atkinson EJ, Foundation M (1997) An introduction to recursive partitioning using the RPART routines. In: Technical Report 61. Mayo Foundation, Rochester, Minnesota. Available at http://www.mayo.edu/hsr/techrpt/61.pdf

  • Tjiong MY, van der Vange N, ten Kate FJ, Tjong AHSP, ter Schegget J, Burger MP, Out TA (1999) Increased IL-6 and IL-8 levels in cervicovaginal secretions of patients with cervical cancer. Gynecol Oncol 73:285–291

    Article  PubMed  CAS  Google Scholar 

  • Vazquez-Ortiz G, Ciudad CJ, Pina P, Vazquez K, Hidalgo A, Alatorre B, Garcia JA, Salamanca F, Peralta-Rodriguez R, Rangel A, Salcedo M (2005) Gene identification by cDNA arrays in HPV-positive cervical cancer. Arch Med Res 36:448–458

    Article  PubMed  CAS  Google Scholar 

  • Veerapaneni P, Kirma N, Nair HB, Hammes LS, Hall KL, Tekmal RR (2009) Elevated aromatase expression correlates with cervical carcinoma progression. Gynecol Oncol 114:496–500

    Article  PubMed  CAS  Google Scholar 

  • Verhoog NJ, Du Toit A, Avenant C, Hapgood JP (2011) Glucocorticoid-independent repression of tumor necrosis factor (TNF) alpha-stimulated interleukin (IL)-6 expression by the glucocorticoid receptor: a potential mechanism for protection against an excessive inflammatory response. J Biol Chem 286:19297–19310

    Article  PubMed  CAS  Google Scholar 

  • Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442

    Article  PubMed  Google Scholar 

  • Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Lu M, Qian J, Yang Y, Li S, Lu D, Yu S, Meng W, Ye W, Jin L (2009) Rationales, design and recruitment of the Taizhou Longitudinal Study. BMC Public Health 9:223

    Article  PubMed  Google Scholar 

  • Wei LH, Kuo ML, Chen CA, Cheng WF, Cheng SP, Hsieh FJ, Hsieh CY (2001) Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor. Gynecol Oncol 82:49–56

    Article  PubMed  CAS  Google Scholar 

  • WHO (2010) World Health Organization. International histological classification of tumours. Available at http://www.who.int/classifications/icd/en/

  • Zhang H, Bonney G (2000) Use of classification trees for association studies. Genet Epidemiol 19:323–332

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the funds from “China’s Thousand Talents Program” Recruitment at Fudan University and by the Shanghai Committee of Science and Technology, China (Grant No. 12DZ2260100). We would like to thank Ya-Jun Yang and Jiu-Cun Wang from Fudan University for the DNA samples of 511 controls originated from the TZL. We also thank Yu-Hu Xin and Hong-Yu Gu from Fudan University Shanghai Cancer Center for the technical and immunohistochemical support, respectively.

Conflict of interest

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China

    Ting-Yan Shi, Mei-Ling Zhu, Jing He, Meng-Yun Wang, Qiao-Xin Li, Xiao-Yan Zhou & Qingyi Wei

  2. Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China

    Xiao-Yan Zhou & Meng-Hong Sun

  3. Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China

    Zhi-Ming Shao & Ke-Da Yu

  4. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China

    Xi Cheng & Xiaohua Wu

  5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Ting-Yan Shi, Mei-Ling Zhu, Jing He, Meng-Yun Wang, Qiao-Xin Li, Xiao-Yan Zhou, Meng-Hong Sun, Zhi-Ming Shao, Ke-Da Yu, Xi Cheng & Xiaohua Wu

  6. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Qingyi Wei

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  1. Ting-Yan Shi
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  11. Xiaohua Wu
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Corresponding authors

Correspondence to Xiaohua Wu or Qingyi Wei.

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T.-Y. Shi and M.-L. Zhu contributed equal to this work.

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Shi, TY., Zhu, ML., He, J. et al. Polymorphisms of the Interleukin 6 gene contribute to cervical cancer susceptibility in Eastern Chinese women. Hum Genet 132, 301–312 (2013). https://doi.org/10.1007/s00439-012-1245-4

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  • DOI: https://doi.org/10.1007/s00439-012-1245-4

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