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.