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

  • Epidemiology
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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.

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Abbreviations

BC:

Breast cancer

BRCA1:

Breast cancer 1

BRCA2:

Breast cancer 2

CI:

Confidence interval

ER:

Estrogen receptor

FGF:

Fibroblast growth factor

HWE:

Hardy–Weinberg equilibrium

OR:

Odds ratio

PCR–RFLP:

Polymerase chain reaction–restriction fragment length polymorphism

SNP:

Single nucleotide polymorphism

VEGF:

Vascular endothelial growth factor

VEGFR1:

Vascular endothelial growth factor receptor 1

sVEGFR1:

Soluble vascular endothelial growth factor receptor 1

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Acknowledgments

This work was supported in part by Grants from the Ministerio de Salud Carlos III and the Foundation Gent x Gent to A.Ll and Consellería de Sanidad [GE-004/09] to P.E. P.R. holds a Santiago Grisolia fellowship from the Conselleria de Sanidad Valenciana, J. F is founded from the RTICC RD06/0020/0080, E. T. from the Grant PS09/01700 and P. E. from the Instituto de Salud Carlos III under a ‘Miquel Servet’ contract [FIS03/0090]. We thank the Biobanco FIHCUV-INCLIVA for providing the paraffin-embedded samples.

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Authors and Affiliations

  1. Fundación Investigación Hospital Clínico Universitario/INCLIVA, Av. Blasco Ibáñez 17, 46010, Valencia, Spain

    Patricia Rodrigues, Jessica Furriol, Eduardo Tormo, Sandra Ballester, Ana Lluch & Pilar Eroles

  2. Servicio de Hematología y Oncología Médica, Hospital Clínico Universitario de Valencia, Av. Blasco Ibáñez 17, 46010, Valencia, Spain

    Ana Lluch

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  1. Patricia Rodrigues
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Correspondence to Pilar Eroles.

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Rodrigues, P., Furriol, J., Tormo, E. et al. The single-nucleotide polymorphisms +936 C/T VEGF and −710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population. Breast Cancer Res Treat 133, 769–778 (2012). https://doi.org/10.1007/s10549-012-1980-1

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