title: Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics.
abstract: BACKGROUND
  Breast cancer is a profoundly heterogeneous disease with respect to biologic and clinical behavior. Gene-expression profiling has been used to dissect this complexity and to stratify tumors into intrinsic gene-expression subtypes, associated with distinct biology, patient outcome, and genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes.
  
  
  METHODS
  We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer.
  
  
  RESULTS
  We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis.
  
  
  CONCLUSIONS
  Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may prove useful for understanding the mechanisms of tumor development and for prognostic and treatment prediction purposes.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Barngatan 2B, 5 Lund, Sweden. goran_b.jonsson@med.lu.se
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Johan
authors.initials: J
authors.lastname: Vallon-Christersson
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.forename: Karolina
authors.initials: K
authors.lastname: Holm
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hegardt
authors.forename: Haukur
authors.initials: H
authors.lastname: Gunnarsson
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.forename: Carina
authors.initials: C
authors.lastname: Strand
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Lena
authors.initials: L
authors.lastname: Luts
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.forename: Oskar Th
authors.initials: OT
authors.lastname: Johannsson
authors.forename: Adalgeir
authors.initials: A
authors.lastname: Arason
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Rosa B
authors.initials: RB
authors.lastname: Barkardottir
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018295:Neoplasms, Basal Cell / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015996:Survival Rate
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor