Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.