title: High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer.
abstract: BACKGROUND
  HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group, needed to be further characterized in large sample sets.
  
  
  METHODS
  Genome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail.
  
  
  RESULTS
  The HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors.
  
  
  CONCLUSIONS
  We have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, Lund, Sweden. johan.staaf@med.lu.se
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.forename: Johan
authors.initials: J
authors.lastname: Vallon-Christersson
authors.forename: Dorthe
authors.initials: D
authors.lastname: Grabau
authors.forename: Adalgeir
authors.initials: A
authors.lastname: Arason
authors.forename: Haukur
authors.initials: H
authors.lastname: Gunnarsson
authors.forename: Bjarni A
authors.initials: BA
authors.lastname: Agnarsson
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Malmström
authors.forename: Oskar Th
authors.initials: OT
authors.lastname: Johannsson
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
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; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases
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