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Background.Caveolin-1, which has been proposed as a candidate tumor suppressor, plays a regulatory role in several signaling pathways.The aim of this study is to evaluate the association between oral cancer susceptibility and Cav-1 genotypes.In this hospital—based case—control study, the association of Cav-1 polymorphisms with oral cancer risk in a Central Taiwanese population was investigated.Methods.Six hundred patients with oral cancer and 620 age-and gender-matched healthy controls recruited were genotyped and analyzed by PCR-RFLP method.Results.There were significant differences between oral cancer and control groups in the distributions of their genotypes (P=l.7× 10-18 and 2.6× 10-4) and allelic frequencies (P=3.3 × 10-19 and 9.5× 10-6) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively.As for the combined genotype analysis, those who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a 0.72-fold (95% confidence interval=0.52-0.99) decreased risk of oral cancer compared to those with GG/TT, while those of any other eornbinations were of increased risk.The presence of metastasis was also correlated to both Cav-1 G14713A AA and Cav-1 T29107ATT genotypes.Conclusions.This is the first report providing evidence that Car-1 being involved in oral cancer, the A allele of the Cav-1 G14713A is risky, the A allele of the Cav-1 T29107A is protective, and AA/TT on these two polymorphisms may be the most risky combined genotype for the development of oral cancer and may be novel risky markers for early detection and prediction of distant metastasis.