title: Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer.
abstract: BACKGROUND
  PPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma (BC) that exhibits poor survival. This subgroup also exhibited amplification of a chromosome region containing the Cyclin D1 coding gene, CCND1. Therefore, we aimed to investigate whether a combination of PPP2R2A (B55α) and Cyclin D1 expression statuses evaluated by immunohistochemistry (IHC) could define a subgroup of luminal BC that exhibits poor survival.
  
  
  METHODS
  First we conducted a retrospective cohort study using sequencing data from The Cancer Genome Atlas initiative to correlate PPP2R2A copy number alteration (CNA) status with its expression level and the corresponding overall survival (OS). Next, also using a retrospective cohort study design, we evaluated the PPP2R2A (B55α) expression levels by IHC in a total of 807 BC patients from two independent cohorts (discovery cohort n = 349 and validation cohort n = 458). Cyclin D1 expression was also evaluated, and the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.
  
  
  RESULTS
  Deletions in the PPP2R2A gene strongly correlate with lower mRNA expression and poorer OS. PPP2R2A (B55α)(-/low) carcinomas have significantly shorter DFS and OS. Furthermore, in univariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.
  
  
  CONCLUSIONS
  We demonstrate that BCs harboring PPP2R2A deletions are associated with worse OS. Moreover, this is the first study to demonstrate that the combination of altered PPP2R2A (B55α) and high Cyclin D1 expression by IHC defines a subgroup of luminal-like BC patients with a high risk of relapse and death.
authors: IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr, Roberto Frias, s/n, 4200-465 Porto, Porto, Portugal. francisco.beca@hms.harvard.edu.|Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215-5450, USA. francisco.beca@hms.harvard.edu.
authors: Francisco
authors: F
authors: Beca
authors: Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston, MA, 02114, USA. miguelmspereira@gmail.com.
authors: Miguel
authors: M
authors: Pereira
authors: Complexo Hospitalar Universitario de Vigo (CHUVI), Rua de Pizarro, 22, 362004, Vigo, Spain. videoprimaria@mundo-r.com.
authors: Jorge F
authors: JF
authors: Cameselle-Teijeiro
authors: IBMC - Instituto de Biologia Molecular e Celular da Universidade do Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal. dmartins@ibmc.up.pt.
authors: Diana
authors: D
authors: Martins
authors: Department of Pathology and Medicine, Laboratorie National de Sante 1, Rue Louis Reche, L-3555, Dudelange, Luxembourg. fschmitt@ipatimup.pt.
authors: Fernando
authors: F
authors: Schmitt
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: C530104:CCND1 protein, human; C512974:PPP2R2A protein, human; D019938:Cyclin D1; D054648:Protein Phosphatase 2