The low VEGF production allele of the +936C/T polymorphism is strongly associated with increased risk for oral cancer.

PURPOSE: Based on the well-established role of vascular endothelial growth factor (VEGF) in tumor-associated angiogenesis in several cancer types and its undefined role in oral oncogenesis, we investigated the possible association of an expression-regulating polymorphism (+936C/T) with risk for oral squamous cell carcinoma (OSCC). METHODS: We studied the allele frequencies of the +936C/T polymorphism in DNA samples of 144 patients with OSCC and 153 healthy controls matched by age, gender and ethnicity, using restriction fragment length polymorphism typing analysis. RESULTS: The low-expression T allele was significantly increased in the total patient group compared to controls (P = 0.008), due to a significant over-representation of C/T heterozygotes compared to C/C homozygotes (P = 0.007). The same pattern was observed in most patient subgroups and more noticeably in patients with a positive family history of cancer (P = 0.001). Interestingly, the increase in T allele frequency was only significant in patients at cancer stages I and II (P = 0.006). CONCLUSIONS: This study clearly indicates that the low-VEGF-production T allele is strongly associated with increased risk for OSCC. In addition, the impressive T allele frequency increment in patients with a positive family cancer history suggests that this allele may also be involved in other malignancies. The fact that this significant increase was observed only in patients with early cancer stages may imply that low VEGF levels might hinder subsequent tumorigenesis. Our findings might be the result of either unidentified properties of the +936 C/T polymorphism or of a strong linkage disequilibrium between this polymorphism and another genetic locus.

Strong association of interleukin-6 -174 G>C promoter polymorphism with increased risk of oral cancer.

In view of the recently found contribution of factors associated with thrombosis and inflammation to carcinogenesis, we investigated the possible association of interleukin-6 (IL-6) with an increased risk of oral cancer. In DNA samples of 162 patients with oral squamous cell carcinoma and 156 healthy controls of comparable ethnicity, age and sex, we studied the -174 G>C polymorphism in the IL-6 gene, which affects its transcription. C allele frequencies were significantly increased in patients compared to controls, 42.6% versus 23.1% (p<0.001). The CC homozygotes had a 7-fold greater risk of developing oral cancer (odds ratio 7.39, 95% CI 2.61-20.92), while the GC heterozygotes had a 4-fold greater risk (odds ratio 3.74, 95% CI 2.29-6.11). A significant increase in C alleles was observed in patients regardless of their smoking or alcohol consumption habits, early or advanced stage of cancer, and presence or absence of a family history for cancer or thrombophilia (p<0.001; Fisher's exact test). These findings suggest that the -174 G>C polymorphism, by affecting IL-6 gene expression, is strongly associated with oral oncogenesis.