Abstract
PURPOSE: Functional DNA polymorphisms affecting gene expression and serum or saliva levels of interleukins IL-1 beta,-4,-6,-8,-10 and tumor necrosis factors TNF-alpha,-beta have been associated with increased risk for the development of oral squamous cell carcinoma (OSCC). The present retrospective case-control study examines possible interactions between seven cytokine genotype polymorphisms and their combinatory effect in predicting the occurrence of OSCC in Caucasians. METHODS: Three hundred and thirty Greeks and Germans were studied, consisting of 162 OSCC cases and 168 healthy controls of comparable age, gender, and ethnicity. A series of multivariate logistic regression models, adjusted for age and gender, was constructed in order to assess the contribution of homozygous or heterozygous variant genotypes of polymorphisms IL-1 beta (+3953C/T), IL-4 (-590C/T), IL-6 (-174G/C), IL-8 (-251A/T), IL-10 (-1082A/G), TNF-alpha (-308G/A) and TNF-beta (+252G/A) upon overall, early and advanced stages of OSCC development. RESULTS: The contribution of TNF-alpha and IL-6 was consistent and robust in almost all models constructed. Furthermore, when the mode of inheritance of each variant allele was taken into account in a "biological" multivariate logistic regression model, four polymorphisms emerged as primary predictors for overall stages of OSCC: TNF-alpha (OR = 15.27; 95% CI = 7.30-31.96), IL-6 (OR = 8.33; 95% CI = 3.95-17.58), IL-8 (OR = 3.54; 95% CI = 1.69-7.43) and IL-10 (OR = 2.65; 95% CI = 1.28-5.46). Finally, IL-1 beta, IL-4 and TNF-beta polymorphisms were not primary predictors of OSCC development in all constructed models. CONCLUSIONS: This study revealed the highly significant contributions of two out of seven studied cytokines (IL-6 and TNF-alpha) in the occurrence of OSCC. Based on these findings and previous reports, possible stoichiometrical interactions of cytokines leading to OSCC development are discussed.