title: Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes.
abstract: BACKGROUND
  Germline mutations in the BRCA1 and BRCA2 genes account for a considerable fraction of familial predisposition to breast cancer. Somatic mutations in BRCA1 and BRCA2 have not been found and the involvement of these genes in sporadic tumour development therefore remains unclear.
  
  
  METHODS
  The study group consisted of 67 primary breast tumours with and without BRCA1 or BRCA2 abnormalities. Genomic alterations were profiled by high-resolution (~7 kbp) comparative genome hybridisation (CGH) microarrays. Tumour phenotypes were analysed by immunohistochemistry on tissue microarrays using selected biomarkers (ER, PR, HER-2, EGFR, CK5/6, CK8, CK18).
  
  
  RESULTS
  Classification of genomic profiles through cluster analysis revealed four subgroups, three of which displayed high genomic instability indices (GII). Two of these GII-high subgroups were enriched with either BRCA1- or BRCA2-related tumours whereas the third was not BRCA-related. The BRCA1-related subgroup mostly displayed non-luminal phenotypes, of which basal-like were most prominent, whereas the other two genomic instability subgroups BRCA2- and GII-high-III (non-BRCA), were almost entirely of luminal phenotype. Analysis of genome architecture patterns revealed similarities between the BRCA1- and BRCA2 subgroups, with long deletions being prominent. This contrasts with the third instability subgroup, not BRCA-related, where small gains were more prominent.
  
  
  CONCLUSIONS
  The results suggest that BRCA1- and BRCA2-related tumours develop largely through distinct genetic pathways in terms of the regions altered while also displaying distinct phenotypes. Importantly, we show that the development of a subset of sporadic tumours is similar to that of either familial BRCA1- or BRCA2 tumours. Despite their differences, we observed clear similarities between the BRCA1- and BRCA2-related subgroups reflected in the type of genomic alterations acquired with deletions of long DNA segments being prominent. This suggests similarities in the mechanisms promoting genomic instability for BRCA1- and BRCA2-associated tumours, possibly relating to deficiency in DNA repair through homologous recombination. Indeed, this feature characterized both familial and sporadic tumours displaying BRCA1- or BRCA2-like spectrums of genomic alterations. The importance of these findings lies in the potential benefit from targeted therapy, through the use of agents leading to DNA double-strand breaks such as PARP inhibitors (olaparib) and cisplatin, for a much larger group of patients than the few BRCA1 and BRCA2 germline mutation carriers.
authors: Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland. oas@hi.is
authors: Olafur Andri
authors: OA
authors: Stefansson
authors: Jon Gunnlaugur
authors: JG
authors: Jonasson
authors: Oskar Thor
authors: OT
authors: Johannsson
authors: Kristrun
authors: K
authors: Olafsdottir
authors: Margret
authors: M
authors: Steinarsdottir
authors: Sigridur
authors: S
authors: Valgeirsdottir
authors: Jorunn Erla
authors: JE
authors: Eyfjord
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017384:Sequence Deletion
chemical_list: D014408:Biomarkers, Tumor