Molecular and Cellular Biochemistry

, Volume 379, Issue 1–2, pp 181–190 | Cite as

Epistatic interaction of Arg72Pro TP53 and −710 C/T VEGFR1 polymorphisms in breast cancer: predisposition and survival

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


The tumour-suppressor gene TP53 has been associated with the angiogenic pathway by a TP53 response element sequence of the VEGFR1 promoter. Within that sequence, the polymorphism −710 C/T VEGFR1, which confers variable transcriptional activation by TP53, has been identified. Our group found an association between this polymorphism and breast cancer (BC) risk. We decided to investigate a possible epistatic interaction between this polymorphism and others located at gene TP53. We chose four polymorphisms (Ex4 + 119G > C, IVS4-91A > G, IVS6 + 62A > G and IVS7 + 92T > G) to analyse out of a total of 461 controls and 453 BC patients in a Spanish population. The two-locus combined analysis of TP53 and 710 C/T VEGFR1 polymorphisms was performed with the multifactor dimension reduction approach. Kaplan–Meier disease-free survival curves were calculated using the SPSS package. Carriers of at least one Pro allele of the Ex4 + 119G > C TP53 polymorphism presented a significant BC risk [OR = 1.34, (95 % CI 1.03–1.75), p value = 0.029]. The epistatic gene–gene analysis showed that the best two-locus model was the combination between Ex4 + 119G > C TP53 and 710 C/T VEGFR1 showing OR of 1.44 (95 % CI 1.10–1.88, p value = 0.0083). Moreover, the Pro/Pro genotypes of Ex4 + 119G > C were associated with poor disease-free survival (p value = 0.013). We conclude that the Ex4 + 119G > C TP53 polymorphism is an independent, low penetrance marker of BC risk in this population. In addition, our findings suggest that the combination of Ex4 + 119G > C TP53 and 710 C/T VEGFR1 genotypes confers a higher risk to develop BC. Also, a possible association of the Ex4 + 119G > C TP53 genotype with decreased disease-free survival in these patients is proposed.


TP53 VEGFR1 Breast cancer Polymorphisms Epistatic 

List of Abbreviations


Breast cancer


Breast cancer 1


Breast cancer 2


Confidence Interval


Cross-validation consistency


Disease-free survival


Hardy–Weinberg equilibrium




Multifactor dimensionality reduction


Odds ratio


Single-nucleotide polymorphism


Tumour-suppressor 53


Vascular endothelial growth factor receptor 1



This work was supported in part by Grants from the Ministerio de Salud Carlos III, the Consellería de Sanidad [GE-004/09] and the Foundation Gent x Gent to AL and PE. PR holds a Santiago Grisolia fellowship from the Conselleria de Sanidad Valenciana. JF is funded by the RTICC RD06/0020/0080. ET receives funds from grant PS09/01700. PE is supported by the Instituto de Salud Carlos III under a ‘Miquel Servet’ contract [FIS03/0090].

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Patricia Rodrigues
    • 1
  • Jessica Furriol
    • 1
  • Eduardo Tormo
    • 1
  • Sandra Ballester
    • 1
  • Ana Lluch
    • 1
    • 2
  • Pilar Eroles
    • 1
  1. 1.Institute of Health Research INCLIVAValenciaSpain
  2. 2.Department of Haematology and Medical OncologyUniversity Hospital of ValenciaValenciaSpain

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