Influence of VEGF-A gene variation and protein levels in breast cancer susceptibility and severity.
Vascular endothelial growth factor-A (VEGF-A) plays an important role in tumour angiogenesis and cancer progression. VEGF gene variation may influence VEGF levels and therefore cancer susceptibility and progression. We studied the role of VEGF single nucleotide polymorphisms and haplotypes in breast cancer susceptibility and severity. We also studied the relationships of VEGF SNPs with circulating VEGF levels in healthy volunteers and protein expression in breast cancers. Single nucleotide polymorphisms (SNPs) in the regulatory regions of the VEGF gene were genotyped by high throughput methods in approximately 500 breast cancer cases and 500 appropriate controls. Haplotype frequencies were inferred using methods based on the Expectation Maximisation algorithm. The effect of VEGF genotypes on serum and plasma VEGF levels were studied in another cohort of healthy individuals. A semi-quantitative assessment of VEGF protein expression on tissue micro arrays (TMA) constructed from approximately 300 breast cancer samples was performed and compared with VEGF genotypes and with histopathological parameters and survival in breast cancer. The -460T/+405C/-7C/936C haplotype in the VEGF gene was found to be associated with decreased breast cancer risk (p = 0.029). The -7C>T polymorphism may influence overall breast cancer survival (p = 0.027). Individual polymorphisms however did not affect breast cancer susceptibility. There was no association between the individual polymorphisms and circulating VEGF levels in healthy volunteers and VEGF expression on the breast cancer micro array. VEGF expression in breast cancers was however associated with high grade (p = 0.002) and ER negative tumours (p = 0.03).