Single nucleotide polymorphisms of the vascular endothelial growth factor gene associated with incidence of oral squamous cell carcinoma Peer W. Ka¨mmerer 1 , Takeshi Toyoshima 1,2 , Sami Eletr 1 , Philipp Ka¨mmerer 1 , Kathrin Kuhr 3 , Bilal Al-Nawas 1 , Ju¨rgen Brieger 4 1 Department of Oral and Maxillofacial Surgery, Johannes Gutenberg-University Mainz, Mainz, Germany; 2 Department of Oral and Maxillofacial Surgery, Kyushu University, Kyushu, Japan; 3 Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Johannes Gutenberg-University Mainz, Mainz, Germany; 4 Department of Otorhinolaryngology, Johannes Gutenberg-University Mainz, Mainz, Germany BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in promoting angiogen- esis and is overexpressed in several malignancies. Poly- morphisms of the VEGF gene can alter VEGF protein expression, which may be biologically significant and ac- count for heterogeneity in disease risk and outcome. The aim of this case–control study was to evaluate potential associations between single nucleotide polymorphisms (SNP) of the VEGF gene with susceptibility of oral squa- mous cell carcinoma (OSCC). PATIENTS AND METHODS: Five VEGF SNP ()1154 G/A, +405 G/C, +936 C/T, )2578 C/A and )460 C/T) were determined in peripheral blood isolated from 80 patients with OSCC and from 40 age- and gender-matched heal- thy volunteers (RT-PCR). RESULTS: The +936 T allele and the )2578 C ⁄ A SNP were expressed significantly more often in the OSCC- group (P = 0.002; P < 0.0001) where three associations between two SNPs (+936 and +405, )2578 and )1154, )460 and )2578) were found. CONCLUSION: Our findings provide support that +936 T allele and )2578 C/A SNP of the VEGF gene alone or in combination with other SNP are associated with OSCC. The SNPs may be used as biomarker for the develop- ment of specialized anti-VEGF drugs. Further studies must confirm the value of preoperative genetic analysis for prognosis. J Oral Pathol Med (2010) 39: 786–792 Keywords: case–control study; oral squamous cell carcinoma; RT-PCR; single nucleotide polymorphism; vascular endothelial growth factor Introduction Oral cancer imposes a considerable problem worldwide being a highly lethal and disfiguring disease (1). The definition of oral cancer implies a neoplasm in the oral cavity, which begins at the lip and ends at the anterior pillar of the fauces (2). According to the report of the World Health Organization (3), oral cancer is the sixth most common cancer worldwide and the most common intraoral subtype is squamous cell carcinoma (OSCC) (4). In the development, the growth and the progression of solid malignancies, independent of localization, angiogenesis has been shown to be a prerequisite (5). The vascular endothelial growth factor (VEGF) plays an important role in angiogenesis. The VEGF gene is located on chromosome 6 at location 6p12.1 (6) and consists of eight exons that exhibit alternate splicing to form a family of proteins (7). VEGF is a potent endothelial cell mitogen which binds specifically to VEGF receptor tyrosine kinase on endothelial cells where it initiates intracellular signal transduction path- ways to mediate angiogenesis and vascular permeability. Hereby, the tumor is provided with new vessels, oxygen and nutrients as well as access to the circulation, facilitating metastasis. In addition to stimulate angio- genesis, it is possible that VEGF may have autocrine functions, acting as a survival factor for tumor cells to protect them from various forms of stress and apoptosis (8, 9). In human tumors (for example, breast, non-small cell lung, colorectal and prostate cancer), VEGF is frequently overexpressed (10–13) and higher levels of VEGF have shown to be related with adverse prognosis Correspondence: Peer W. Ka¨mmerer, MD, Department of Oral and Maxillofacial Surgery, Johannes Gutenberg-University, Augustusplatz 2, 55131 Mainz, Germany. Tel-business: 00496131-175086, Tel-home: 0049178-4571508, Fax: 00496131 ⁄ 17-6602, E-mail: kaemmerer@mkg. klinik.uni-mainz.de Accepted for publication March 15, 2010 J Oral Pathol Med (2010) 39: 786–792 ª 2010 John Wiley & Sons A/S Æ All rights reserved wileyonlinelibrary.com/journal/jop doi: 10.1111/j.1600-0714.2010.00904.x