title: Variants on the promoter region of PTEN affect breast cancer progression and patient survival.
abstract: BACKGROUND
  The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.
  
  
  METHODS
  We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.
  
  
  RESULTS
  All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.
  
  
  CONCLUSIONS
  Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, 00029 HUS, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Pelttari
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality*; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis
chemical_list: D051059:PTEN Phosphohydrolase