title: Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival.
abstract: BACKGROUND
  Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.
  
  
  METHODS
  Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.
  
  
  RESULTS
  Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.
  
  
  CONCLUSIONS
  These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Alvarez
authors.affiliation: Mathomics, Center for Mathematical Modeling (UMI 2807 CNRS) and Center for Genome Regulation (Fondap 15090007), University of Chile, Santiago, Chile.|Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, 34134, Turkey.
authors.forename: Andrés
authors.initials: A
authors.lastname: Aravena
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Teresa
authors.initials: T
authors.lastname: Tapia
authors.affiliation: Laboratory of Molecular Technology Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD, USA.
authors.forename: Ester
authors.initials: E
authors.lastname: Rozenblum
authors.affiliation: Department of Anatomo-Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Luisa
authors.initials: L
authors.lastname: Solís
authors.affiliation: Department of Anatomo-Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Corvalán
authors.affiliation: Cancer Center, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Camus
authors.affiliation: Clinica Las Condes, Santiago, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Laboratory of Molecular Technology Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Munroe
authors.affiliation: Mathomics, Center for Mathematical Modeling (UMI 2807 CNRS) and Center for Genome Regulation (Fondap 15090007), University of Chile, Santiago, Chile.|Department of Mathematical Engineering, University of Chile, Santiago, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Maass
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile. pcarvallo@bio.puc.cl.
authors.forename: Pilar
authors.initials: P
authors.lastname: Carvallo
mesh_terms: D019313:BRCA1 Protein / Q000096:biosynthesis / Q000235:genetics*; D024682:BRCA2 Protein / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D009363:Neoplasm Proteins
keywords: Array CGH; BRCAX; Breast cancer; Genomic gains; Genomic losses; Oncogenes; Tumor suppressor