Among the possible genetic contributors to cancer-related venous thromboembolism (VTE), vascular endothelial growth factor (VEGFA) could play an important role, as an imbalance of the VEGFA system (either disease-related or drug-induced) may result in a disturbance of vascular homeostasis. Thus, this study was designed to investigate the predictive role of eight different VEGFA gene promoter single nucleotide polymorphisms (SNPs) for a first VTE episode in cancer out-patients undergoing chemotherapy. To this purpose, VEGFA gene promoter polymorphisms were analysed in 297 cancer patients using polymerase chain reaction amplification and direct DNA sequencing analysis. One hundred forty unrelated healthy subjects from the same geographical area were also analysed in order to evaluate and compare genotype/haplotype frequencies in our ethnicity. VTE occurred in 26 (9%) of cancer patients with a median time-to-event of 3.4 months. Association analyses showed that -1154G/A polymorphism was significantly associated with the risk of chemotherapy-triggered VTE, with the A allele exerting a protective role both in the overall population (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.07-0.58) or in bevacizumab-treated metastatic patients (HR: 0.09, 95%CI: 0.01-0.86) in whom VEGFA -1154AA genotype also conferred a reduced risk of early progression (HR: 0.58, 95%CI: 0.34-0.98). These results suggest that VEGFA may represent a candidate gene contributing to VTE development in chemotherapy treated cancer patients and that -1154G/A SNP might provide useful clinical information on the efficacy and toxicity of bevacizumab in metastatic patients. Validation studies are needed for translation into clinical practice.
Keywords: Venous thromboembolism; chemotherapy; risk prediction; single nucleotide polymorphisms; vascular endothelial growth factor.