Molecular Pathways The Role of Vascular Endothelial Growth Factor Genetic Variability in Cancer

Angiogenesis is a hallmark of tumor pathogenesis. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and its inhibition has become a successful approach to antitumor therapy across tumor types. The VEGF gene is highly polymorphic with multiple common single nucleotide polymorphisms (SNPs) in the promoter, 5′ untranslated region and 3′ untranslated region. There is evidence that these SNPs in the regulatory regions can affect VEGF expression. In vitro and in vivo data show that genetic variability affects the activity and expression of VEGF. Case-control and cohort studies suggest that genetic variability may affect risk and outcome of a variety of disease states that are tightly regulated by angiogenesis. Recently, genetic variability in VEGF has been studied as a potential predictive biomarker for bevacizumab. The VEGF-1154 AA and -2578 AA genotypes predicted an improved median overall survival, whereas the VEGF-634 CC and -1498 TT genotypes predicted protection from grade 3-4 hypertension in the pivotal trial, E2100. If validated, these finding could help direct which subgroup of patients should receive bevacizumab. (Clin Cancer Res 2009;15(17):5297–302)