title: Association of vascular endothelial growth factor--a gene polymorphisms and haplotypes with breast cancer metastases.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF-A) is a key regulator of tumor-induced angiogenesis and essential for tumor growth and distant tumor spread. The aim of the present study was to evaluate the role of VEGF-A polymorphisms and haplotypes for metastatic progression in breast cancer patients.
  
  
  METHODS
  We performed a prospective study including 801 breast cancer patients. Occurrence of metastases was examined in regular follow-up investigations. Seven VEGF-A polymorphisms were selected and determined by 5'-nuclease assays (TaqMan). The selection of VEGF-A variants was based upon their location (promoter or UTR) as well as a minor allele frequency of at least 0.10. Haplotypes and linkage disequilibrium were determined using the Haploview program.
  
  
  RESULTS
  Within a median follow-up time of 84 months, 165 (21%) patients developed distant metastases. In univariate analysis, carriers of the CCCCC haplotype formed by five polymorphisms upstream the coding region were at decreased risk of distant metastases [hazard ratio (HR)=0.743; 95% CI 0.579-0.953; p=0.019]. Univariate analysis also revealed a decreased risk of distant metastases for postmenopausal patients carrying the -634G>C polymorphism (HR 0.704; 95% CI 0.514-0.965; p=0.029) and the CCCCC haplotype (HR=0.645; 95% CI 0.464-0.898; p=0.009). After adjustment for other co-variates, the HR for distant metastases was 0.651 (95% CI 0.447-0.948) for postmenopausal carriers of the -634G>C polymorphism (p=0.025; corrected p-value=0.262), and 0.586 (95% CI 0.393-0.873) for postmenopausal patients with the CCCCC haplotype (p=0.009, corrected p-value=0.189).
  
  
  CONCLUSIONS
  The results from univariate and multivariate analyses suggest an influence of VEGF-A gene variants on the development of distant metastases in breast cancer patients. However, none of the observed associations reached statistical significance after correction for the effects of multiple testing. Additional prospective and sufficiently powered studies are essential before firm conclusions about the role of VEGF-A gene variants for distant progression in breast cancer can be drawn.
authors.affiliation: Division of Internal Medicine, GKK Outpatient Department , Graz , Austria.
authors.forename: Uwe
authors.initials: U
authors.lastname: Langsenlehner
authors.forename: Günter
authors.initials: G
authors.lastname: Hofmann
authors.forename: Wilfried
authors.initials: W
authors.lastname: Renner
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.forename: Sabine
authors.initials: S
authors.lastname: Krenn-Pilko
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Thurner
authors.forename: Peter
authors.initials: P
authors.lastname: Krippl
authors.forename: Tanja
authors.initials: T
authors.lastname: Langsenlehner
mesh_terms: D000704:Analysis of Variance; D001859:Bone Neoplasms / Q000556:secondary; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D012878:Skin Neoplasms / Q000556:secondary; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A