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Background  Oral cancer, which is the fourth most common male cancer, is associated with environmental carcinogens in Taiwan. Vascular endothelial growth factor (VEGF)-C, an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies. This study was designed to examine associations of five  VEGF-C  gene polymorphisms with the susceptibility to and clinicopathological characteristics of oral squamous cell carcinoma.    Methodology/Principal Findings  Five single-nucleotide polymorphisms (SNPs) of  VEGF-C  were analyzed by a real-time polymerase chain reaction (PCR) in 470 male patients with oral cancer and 426 cancer-free controls. In this study, we found that the  VEGF-C  rs7664413 and rs2046463 polymorphisms were associated with oral-cancer susceptibility but not with any clinicopathological parameters. The  GGACA  or  GACTG  haplotype of five  VEGF-C  SNPs (rs3775194, rs11947611, rs1485766, rs7664413, and rs2046463) combined was also related to the risk of oral cancer. Among 611 male smokers,  VEGF-C  polymorphism carriers who also chewed betel quid were found to have a 14.5–24.2-fold risk of having oral cancer compared to the  VEGF-C  wild-type carrier who did not chew betel quid. Among 461 male betel-quid chewers,  VEGF-C  polymorphism carriers who also smoked had a 2.7–18.1-fold risk of having oral cancer compared to those who carried the wild type but did not smoke.    Conclusions  Our results suggest that the two SNPs of  VEGF-C  (rs7664413 and rs2046463) and either of two haplotypes of five SNPs combined have potential predictive significance in oral carcinogenesis. Gene-environmental interactions among  VEGF-C  polymorphisms, smoking, and betel-quid chewing might alter one's susceptibility to oral cancer.

Impact of VEGF-C Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan