The single-nucleotide polymorphisms +936 C/T VEGF and −710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population

Abstract

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. The association between polymorphisms of angiogenesis pathway genes and risk of breast cancer (BC) has been widely studied, but the results are not conclusive. This information is especially limited in Spanish women, so we decided to conduct a case-control study. Here, we selected four commonly studied polymorphisms in VEGF, rs3025039 (known as +936 C/T), rs1109324, rs154765 and rs833052, one polymorphism at the promoter of the VEGFR1 (-710 C/T) and another in the FGF2, rs1449683, gene to explore their association with BC susceptibility. Genotyping was performed by TaqMan SNP assays and polymerase chain reaction-restriction fragment length polymorphis (PCR-RFLP) on 453 patients and 461 controls in a population from Valencia (Spain). We observed that women carriers of +936 CT + TT VEGF genotypes have a protective effect concerning this disease (p = 0.014; OR 0.67, 95% CI 0.48-0.92) in the global group of patients. The haplotype TGAC of VEGF (rs3025039, rs1109324, rs154764 and rs833052) shows a reduction of the risk to develop BC (p = 3e-04; OR 0.48, 95% CI 0.32-0.72). Furthermore, we found that carriers of -710 CT + TT VEGFR1 genotypes have also a protective effect (p = 0.039; OR 0.55, 95% CI 0.31-0.98). When we stratified by groups of ages these associations were maintained. Our data report for the first time the association of the polymorphism -710 C/T VEGFR1 with BC. Additional experiments focused on VEGF-A, VEGFR1 and sVEGFR1 gene expression demonstrated that carriers of T allele at -710 C/T VEGFR1 genotype have higher levels of sVEGFR1/VEGF-A than the C/C genotype carriers. This was consistent with the hypothesis that this polymorphism may act as low penetrance risk factor. The data provided suggest that +936 C/T VEGF and -710 C/T VEGFR1 genotypes are likely important genetic markers of susceptibility to BC.

Association between vascular endothelial growth factor gene polymorphisms and bladder cancer risk

“…The rs1570360 G̸A VEGF polymorphism, but not rs3025039 C̸T, was associated with an increased risk of breast cancer. A case-control study conducted by Rodrigues et al (28) suggested that the VEGF rs3025039 C̸T genotype was likely a key genetic marker of susceptibility to breast cancer in Caucasians. The data obtained from that study also indicated that the VEGF rs833052 C̸A polymorphism was not a susceptibility factor for breast cancer.…”

Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms and Breast Cancer Risk in a Chinese Population

“…The associations between three VEGF gene polymorphisms (-634 G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, and the currently available results are inconclusive (Krippl et al, 2003;Jin et al, 2005;Lu et al, 2005;Jacobs et al, 2006;Kataoka et al, 2006;Eroglu et al, 2008;Jakubowska et al, 2008;Langsenlehner et al, 2008;Schneider et al, 2008;Wehrschuetz et al, 2009;Gu and Wang, 2011;Jin et al, 2011;Liu et al, 2011;Oliveira et al, 2011;Qiu et al, 2011;Wang et al, 2011;Yang et al, 2011;Rodrigues et al, 2012). The aim of this study was to investigate the association between three VEGF gene polymorphisms and breast cancer risk in Chinese Han patients.…”

Association of −2549 Insertion/Deletion Polymorphism of Vascular Endothelial Growth Factor with Breast Cancer in North Indian Patients

“…VEGF-A is highly polymorphic in the promoter and 5¢ untranslated region and single-nucleotide polymorphisms in this region have been reported to regulate VEGF expression via alternative initiation of transcription and internal initiation of translation (Akiri et al, 1998;Huez et al, 1998). Polymorphisms of VEGF have been studied with disparate results in various diseases like type 2 diabetes (Awata et al, 2002;Buraczynska et al, 2007), giant cell arteritis (Rueda et al, 2005), renal complications in Henoch-Schonlein purpura (Rueda et al, 2006), hepatocellular carcinoma (HCC) (Kong et al, 2007), prostate cancer (Onen et al, 2008), familial endometriosis (Zhao et al, 2008), ectopic pregnancy (Elito et al, 2010), glomerulonephritides (Safrankova et al, 2011), hypertension (Kim et al, 2012), age-related macular degeneration (Lu et al, 2012), and breast cancer (Lu et al, 2005;Jacobs et al, 2006;Langsenlehner et al, 2008;Schneider et al, 2008;Rodrigues et al, 2012).…”