title: Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines.
abstract: HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Edurne
authors.initials: E
authors.lastname: Arriola
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchio
authors.forename: David S P
authors.initials: DS
authors.lastname: Tan
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Drury
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Socorro Maria
authors.initials: SM
authors.lastname: Rodriguez-Pinilla
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Narinder
authors.initials: N
authors.lastname: Tamber
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; 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; D023281:Genomics; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D046228:Microarray Analysis; D009693:Nucleic Acid Hybridization; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human