Characterisation of the Genetic Heterogeneity of Invasive Breast Cancers with Heterogeneous HER2 Overexpression and Gene Amplification
Charlotte KY Ng, Arnaud Gauthier, Paul M Wilkerson, Maryou B Lambros, Laurent Arnoud, Magali Lacroix-Triki, Frederique Penault-Llorca, Marie Christine Baranzelli, Xavier Sastre-Garau, Christopher J Lord, Marketa Zvelebil, Costas Mitsopoulos, Alan Ashworth, Rachael Natrajan, Britta Weigelt, Olivier Delattre, Paul Cottu, Jorge S Reis-Filho, Anne Vincent-Salomon. Memorial Sloan-Kettering Cancer Center, New York, NY; Institute of Cancer Research, London, United Kingdom; Institut Curie, Paris, France; Centre Georges François Leclerc, Dijon, France; Institut Claudius Regaud, Toulouse, France; Centre Jean Perrin, Clermont Ferrand, France; Centre Oscar Lambret, Lille, France
Background: In a rare subgroup of breast cancers defined as HER2-positive by immunohistochemistry and/ or in situ hybridisation (ISH) according the ASCO/ CAP guidelines, HER2 overexpression and gene amplification are restricted to a subset of cancer cells (i.e. >30% but <100%). The aim of this study was to define the repertoire of copy number aberrations and somatic mutations in the HER2-positive and HER2-negative components of cases with heterogeneous HER2 overexpression and gene amplification.
Design: HER2-positive breast cancers with >30% but <100% of cells displaying HER2 overexpression were retrieved from the authors' institutions, and the HER2 status was re-assessed using immunohistochemistry and ISH. The HER2-positive and HER2-negative components from each case were microdissected from tissue sections stained with an anti-HER2 antibody. DNA samples extracted from both components of each case were subjected to microarray-based comparative genomic hybridisation (aCGH). The HER2-positive and HER2-negative components of two cases were also subjected to exome sequencing on a HiSeq2000 (60x) and the results were validated using an orthogonal method (i.e. Ion Torrent sequencer, >300x).
Results: The HER2-positive and HER2-negative components of each case displayed gene copy number aberrations in common; however, genomic changes restricted to either the HER2-positive or HER2-negative component of each case, in addition to 17q12 amplification encompassing the HER2 gene locus, were observed in ten of the twelve cases. Massively parallel sequencing of two cases demonstrated that the HER2-positive and HER2-negative components from each case harboured somatic mutations in common. The HER2-negative components of the cases analysed harboured somatic mutations of HER2 and ROR1, tyrosine kinase receptors, and PTTG1IP, a proto-oncogene with putative ER elements, which were not present in the HER2-positive components.
Conclusions: Although the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification are clonally related, additional genetic aberrations restricted to either the HER2-positive or HER2-negative component of each case were observed, and may constitute potential drivers in the absence of HER2 overexpression/ gene amplification.
Monday, March 4, 2013 11:00 AM
Proffered Papers: Section B, Monday Morning