Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma.
OBJECTIVE
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.
Vairaktaris
Eleftherios
E
Department of Maxillofacial Surgery, University of Athens Medical School, Attikon Hospital, Rimini 1, 12462, Athens, Greece. lvairakt@med.uoa.gr
Yapijakis
Christos
C
Serefoglou
Zoe
Z
Avgoustidis
Dimitrios
D
Critselis
Elena
E
Spyridonidou
Sofia
S
Vylliotis
Antonis
A
Derka
Spyridoula
S
Vassiliou
Stavros
S
Nkenke
Emeka
E
Patsouris
Efstratios
E
D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D007378:Interleukins / Q000235:genetics*; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014408:Biomarkers, Tumor; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4