1. ¹The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
2. ²Department of Biomedical Sciences and Human Oncology, University of Turin, Torino, Italy
3. ³Academic Department of Biochemistry, Royal Marsden Hospital, London, UK
4. ⁴Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
5. ⁵Department of Paediatric Oncology, Institute of Cancer Research, Sutton, UK

Correspondence: Dr JS Reis-Filho, MD, PhD, FRCPath, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. E-mail: Jorge.Reis-Filho@icr.ac.uk

^*Current address: Department of Medical Oncology, Hospital del Mar, Passeig Maritim 25, Barcelona 08003, Spain.

Received 18 July 2007; Revised 4 February 2008; Accepted 10 February 2008; Published online 10 March 2008.

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 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.