title: Epistatic interaction of Arg72Pro TP53 and -710 C/T VEGFR1 polymorphisms in breast cancer: predisposition and survival.
abstract: 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.
authors.affiliation: Institute of Health Research INCLIVA, Valencia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rodrigues
authors.forename: Jessica
authors.initials: J
authors.lastname: Furriol
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tormo
authors.forename: Sandra
authors.initials: S
authors.lastname: Ballester
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.forename: Pilar
authors.initials: P
authors.lastname: Eroles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058011:Multifactor Dimensionality Reduction; D020641:Polymorphism, Single Nucleotide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D040281:Vascular Endothelial Growth Factor Receptor-1