title: The genomic profile of HER2-amplified breast cancers: the influence of ER status.
abstract: Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: C
authors.initials: C
authors.lastname: Marchiò
authors.forename: R
authors.initials: R
authors.lastname: Natrajan
authors.forename: K K
authors.initials: KK
authors.lastname: Shiu
authors.forename: M B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: S M
authors.initials: SM
authors.lastname: Rodriguez-Pinilla
authors.forename: D S P
authors.initials: DS
authors.lastname: Tan
authors.forename: C J
authors.initials: CJ
authors.lastname: Lord
authors.forename: D
authors.initials: D
authors.lastname: Hungermann
authors.forename: K
authors.initials: K
authors.lastname: Fenwick
authors.forename: N
authors.initials: N
authors.lastname: Tamber
authors.forename: A
authors.initials: A
authors.lastname: Mackay
authors.forename: J
authors.initials: J
authors.lastname: Palacios
authors.forename: A
authors.initials: A
authors.lastname: Sapino
authors.forename: H
authors.initials: H
authors.lastname: Buerger
authors.forename: A
authors.initials: A
authors.lastname: Ashworth
authors.forename: J S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D000075223:Poly-ADP-Ribose Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011960:Receptors, Estrogen; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human