title: Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression.
abstract: BACKGROUND
  Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease.
  
  
  METHODS
  Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.
  
  
  RESULTS
  Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.
  
  
  CONCLUSIONS
  The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.
authors.affiliation: Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland.
authors.forename: Olafur A
authors.initials: OA
authors.lastname: Stefansson
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.forename: Kristrun
authors.initials: K
authors.lastname: Olafsdottir
authors.forename: Hordur
authors.initials: H
authors.lastname: Bjarnason
authors.forename: Oskar
authors.initials: O
authors.lastname: Th Johannsson
authors.forename: Sigridur K
authors.initials: SK
authors.lastname: Bodvarsdottir
authors.forename: Sigridur
authors.initials: S
authors.lastname: Valgeirsdottir
authors.forename: Jorunn E
authors.initials: JE
authors.lastname: Eyfjord
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D002882:Chromosomes, Human, Pair 13; D002886:Chromosomes, Human, Pair 17; D002896:Chromosomes, Human, Pair 6; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D019942:Genes, p16; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011003:Ploidies
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D019394:Ki-67 Antigen