A common and functional gene variant in the vascular endothelial growth factor a predicts clinical outcome in early-stage breast cancer

Angiogenesis and cell cycle control play critical roles in breast cancer susceptibility and clinical outcome and are mainly controlled by vascular endothelial growth factor (VEGF) and cyclin-dependent kinases, respectively. Functional germline polymorphisms in these genes alter the function, thereby causing inter-individual differences in breast cancer risk and clinical outcome. In this study, we investigated the influence of the functional polymorphisms VEGF-A rs3025039 C>T and CCND1 rs9344 G>A on risk and clinical outcome in early-stage breast cancer. DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 control subjects was genotyped for these polymorphisms. Genotypes were tested for associations with breast cancer risk and clinical outcome. There was no significant association between the polymorphisms and breast cancer risk. However, the minor allele of VEGF-A rs3025039 C>T was significantly associated with decreased recurrence-free survival (HR 1.845; 95% confidence interval [CI] 1.035-3.290; P=0.038) and remained significant in multivariate analysis (HR 1.880; 95% CI 1.020-3.465; P=0.043). Patients carrying at least one A-allele in CCND1 rs9344 G>A showed a trend towards decreased recurrence-free survival in univariate analysis (HR 2.379; 95% CI 0.841-6.728; P=0.068). This study provides evidence that the functional VEGF-A rs3025039 C>T polymorphism influences recurrence-free survival in early-stage breast cancer.