[103] Characterisation of the Repertoire of Gene Copy Number Changes and Gene Mutations in the Progression from In Situ to Invasive Breast Cancer

Adriana Campion-Flora, Lucia Hernandez, Paul Wilkerson, Maryou B Lambros, Daniel Nava Rodrigues, Arnaud Gauthier, Alan Mackay, Rachael Natrajan, Jorge S Reis-Filho. The Institute of Cancer Research, London, United Kingdom; Institut Curie, Paris, France

Background: The underlying mechanisms of the progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are yet to be fully elucidated. There is evidence to suggest that breast cancers are composed of a mosaic of non-modal cancer cell populations that harbour specific genetic alterations in addition to the founder genetic hits. Progression from DCIS to IDC may be mediated by the selection of a subpopulation of cancer cells with specific genetic aberrations, or by the acquisition of new genetic aberrations including specific copy number aberrations. The aims of this study were to determine the gene copy number aberrations and repertoire of mutations in common oncogenes in matched DCIS and IDC.
Design: Fresh frozen samples of breast cancer containing bona fide areas of DCIS and IDC in the same specimen were retrieved from thirteen patients. Twenty 10μm sections per case were microdissected under a stereomicroscope, with IDC and DCIS components collected separately. DNA was extracted and subjected to i) microarray-based comparative genomic hybridisation (aCGH), and ii) Sequenom Oncocarta v1.0 panel to determine the prevalence of hot-spot mutations in 19 known oncogenes. Fluorescence in situ hybridisation and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively.
Results: In 9 of the 13 cases, the gene copy number profiles and mutational spectrum of matched DCIS and IDC components were strikingly similar. In the remaining four cases, high level gene amplifications of five loci (i.e. 1q41, 2q24, 6q22, 8q21 and 9p13) were either restricted to the IDC component or the number of cells harbouring the amplification were higher in the IDC than in the DCIS component, suggesting enrichment of cells harbouring those amplicons in the IDC component. Sequenom MassArray identified PIK3CA mutations restricted to the DCIS component in two cases, suggesting selection of a clone that did not harbour the mutation in the process of invasion.
Conclusions: Our results provide strong circumstantial evidence to suggest that, in some cases, the progression of DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations, whilst in other cases by the negative selection of clones that harbour specific genetic aberrations (e.g. PIK3CA mutations in oestrogen receptor positive breast cancer). Genetic aberrations other than gene copy number changes or epigenetic aberrations may drive progression from DCIS to IDC in the majority of other cases.
Category: Breast

Tuesday, March 20, 2012 8:00 AM

Platform Session: Section B, Tuesday Morning

 

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