A Common Interleukin-6 Promoter Polymorphism in Patients With Vulvar Cancer

Abstract

Objective: Besides its important role in immune response and inflammatory processes the cytokine interleukin-6 (IL-6) is crucially involved in carcinogenesis. A common polymorphism within the gene encoding IL-6 (IL6) is known to alter IL-6 protein expression and has been associated with patients' prognosis in various malignancies. No data are available with respect to vulvar cancer. Therefore, we determined the prognostic potential of the common -174(G→C) single nucleotide polymorphism in the promoter region of IL6 in a series of patients with this disease.

Methods: The IL6 promoter polymorphism was investigated in 81 Caucasian patients with surgically treated squamous cell vulvar cancer using pyrosequencing. Results were correlated with clinical data.

Results: No association was ascertained between the IL6 promoter polymorphism and the investigated clinicopathologic parameters, ie, tumor stage, lymph node involvement, tumor grade, and patient's age at diagnosis. In an univariate analysis, lymph node involvement and patients' age at diagnosis were associated with patient prognosis. In a multivariate analysis, including tumor stage and lymph node involvement as established prognostic factors and the IL6 promoter polymorphism, lymph node involvement, and the presence of at least one mutant allele, but not tumor stage, were associated with increased disease-free and overall survival.

Conclusion: Our data suggest that the IL6 - 174(G→C) promoter polymorphism might serve as an additional prognostic parameter in patients with vulvar cancer.

Keywords

Vulvar cancer gene polymorphism interleukin-6

Get full access to this article

View all access options for this article.

References

1. Simpson RJ , Hammacher A , Smith DK , Matthews J , Ward LD . Interleukin-6: structure-function relationships. Protein Sci 1997;6:929-955.

2. Partridge M , Chantry D , Turner M , Feldmann M . Production of interleukin-1 and interleukin- 6 by human keratinocytes and squamous cell carcinoma cell lines. J Invest Dermatol 1991;96:771-776.

3. Chen Z , Malhotra PS , Thomas GR , et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999;5:1369-1379.

4. Wang LS , Chow KC , Wu CW . Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate. Br J Cancer 1999;80:1617-1622.

5. Castrilli G , Tatone D , Diodoro MG , Rosini S , Piantelli M , Musiani P . Interleukin 1alpha and interleukin 6 promote the in vitro growth of both normal and neoplastic human cervical epithelial cells. Br J Cancer 1997;75:855-859.

6. Okamoto M , Hattori K , Oyasu R . Interleukin-6 functions as an autocrine growth factor in human bladder carcinoma cell lines in vitro. Int J Cancer 1997;72:149-154.

7. Bihl M , Tamm M , Nauck M , Wieland H , Perruchoud AP , Roth M . Proliferation of human non-small-cell lung cancer cell lines: role of interleukin-6. Am J Respir Cell Mol Biol 1998;19:606-612.

8. Yamaji H , Iizasa T , Koh E , et al. Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer. Cancer Immunol Immunother 2004;53:786-792.

9. Wei LH , Kuo ML , Chen CA , et al. Interleukin-6 in cervical cancer: The relationship with vascular endothelial growth factor. Gynecol Oncol 2001;82:49-56.

10.

10. Yanagawa H , Sone S , Takahashi Y , et al. Serum levels of interleukin 6 in patients with lung cancer. Br J Cancer 1995;71:1095-1098.

11.

11. Wu CW , Wang SR , Chao MF , et al. Serum interleukin-6 levels reflect disease status of gastric cancer. Am J Gastroenterol 1996;91:1417-1422.

12.

12. Scambia G , Testa U , Benedetti Panici P , et al. Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 1995;71:354-356.

13.

13. Scheid C , Young R , McDermott R , Fitzsimmons L , Scarffe JH , Stern PL . Immune function of patients receiving recombinant human interleukin-6 (IL-6) in a phase I clinical study: induction of C-reactive protein and IgE and inhibition of natural killer and lymphokine-activated killer cell activity. Cancer Immunol Immunother 1994;38:119-126.

14.

14. Ishihara K , Hirano T . IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002;13:357-368.

15.

15. Vickers MA , Green FR , Terry C , et al. Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res 2002;53:1029-1034.

16.

16. Bennermo M , Held C , Stemme S , et al. Genetic predisposition of the interleukin-6 response to inflammation: Implications for a variety of major diseases? Clin Chem 2004;50:2136-2140.

17.

17. Cozen W , Gill PS , Ingles SA , et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood 2004;103:3216-3221.

18.

18. Belluco C , Olivieri f , Bonafe M , et al. -174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res 2003;9:2173-2176.

19.

19. Iacopetta B , Grieu F , Joseph D . The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype. Br J Cancer 2004;90:419-422.

20.

20. DeMichele A , Martin AM , Mick R , et al. Interleukin-6-174G→C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 2003;63:8051-8056.

21.

21. Hefler LA , Grimm C , Ackermann S , et al. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res 2003;63:3066-3068.

22.

22. Sturgeon SR , Brinton LA , Devesa SS , Kurman RJ . In situ and invasive vulvar cancer incidence trends (1973 to 1987). Am J Obstet Gynecol 1992;166:1482-1485.

23.

23. Jones RW , Branyai J , Stables S . Trends in squamous cell carcinoma of the vulva: the influence of vulvar intraepithelial neoplasia. Obstet Gynecol 1997;90:448-452.

24.

24. van de Vivjer MJ , He YD , van't Veer LJ , et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.

25.

25. Coussens LM , Werb Z . Inflammtion and cancer. Nature 2002;420:860-867.

26.

26. Fitzpatrick FA . Inflammation, carcinogenesis and cancer. Int Immunopharmacol 2001;1:1651-1667.

27.

27. Ondrey FG , Dong G , Sunwoo J , et al. Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol Carcinog 1999;26:119-129.

28.

28. Hefler LA , Ludwig E , Lebrecht A , et al. Polymorphisms of the interleukin-1 gene cluster and ovarian cancer. J Soc Gynecol Investig 2002;9:386-390.