Strong association of the tissue inhibitor of metalloproteinase-2 polymorphism with an increased risk of oral squamous cell carcinoma in Europeans

The present study was performed in order to investigate the possible association of the -418 G/C polymorphism in the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene, which affects its expression, with the risk of developing oral cancer. PCR-based restriction analysis was performed in DNA samples from 158 patients with oral squamous cell carcinoma (OSCC) and 168 healthy controls of equivalent sex, age and ethnicity (Greeks and Germans). Statistical analyses were performed with Fisher's exact test and the calculation of odds ratios with a 95% confidence interval (CI). The frequency of the low C allele expression was ten times greater in the patients than the controls (31% vs 2.7%, respectively; P<0.001). The C/C and G/C genotypes were associated with an increased risk of developing OSCC (P<0.001, OR=40.88, 95% CI=2.24-744.40, and P<0.001, OR=21.31, 95%=9.82-46.21, respectively). The same pattern of significant differences with the controls was also observed in the subgroups of patients in regard to the initial or advanced stages of oral cancer, family history of any type of cancer or thrombosis, and smoking habits or alcohol abuse. These findings are consistent with the reduced levels of TIMP-2 in the presence of the low expression C allele, which are insufficient to inhibit the matrix metalloproteinase-driven degradation of the extracellular matrix (leading to cancer invasion) and mitogen-driven neoangiogenesis (leading to tumor growth and metastasis). In conclusion, the studied TIMP-2 polymorphism is strongly associated with an increased risk of OSCC in Europeans carrying the low C allele expression. These results indicate that this polymorphism could serve as a genetic marker for the susceptibility of cancer in the oral cavity.