Genomic Analysis of Matched In Situ to Invasive Ductal Carcinomas Provides Direct Evidence for Selection of Invasive Cancer Cells with Specific Genetic Aberrations.
Lucia Hernandez, Maryou B Lambros, Cecilia Cabral, Radost Vatcheva, Alan Mackay, Paul Wilkerson, Rachael Natrajan, Jorge S Reis-Filho. Institute of Cancer Research, London, United Kingdom
Background: The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is reported to be a complex biological phenomenon, whose underlying mechanisms are yet to be fully elucidated. Recent massively parallel sequencing studies have demonstrated that breast cancers are composed of a mosaic of non-modal populations that in addition to the founder oncogenic genetic hits harbour additional genetic aberrations. Here we sought to determine whether the pattern of copy number aberrations between matched DCIS and IDC samples differs and if progression from DCIS to IDC would be mediated by the selection of a subpopulation of cancer cells with specific genetic aberrations or by the acquisition of specific copy number aberrations.
Design: Frozen samples of breast cancer containing in the same specimen bona fide areas of DCIS and invasive carcinomas from 13 patients were retrieved and microdissected under a stereomicroscope. DNA was extracted from microdissected lesions and subjected to microarray-based comparative genomic hybridisation (aCGH) using a 32K bacterial artificial chromosome array platform. Fluorescence and chromogenic in situ hybridisation was performed for selected genomic regions to validate the aCGH findings.
Results: The DCIS components were of grade I, II and III in 1, 4 and 8 cases respectively. 12 were oestrogen receptor (ER) positive and 2 harboured HER2 gene amplification. No differences in histological grade, receptor status or HER2 were observed between matched DCIS and IDC samples. aCGH analysis revealed identical patterns of copy number aberrations in the majority of the matched samples analysed. However, in 4 cases, although the matched DCIS and IDC components harboured similar patterns of genetic aberrations, the IDC component harboured additional copy number aberrations, including amplifications of 7q11, providing direct evidence that the modal population of matched DCIS and IDC samples is not necessarily identical in terms of their repertoire of copy number aberrations. These results were confirmed by in situ hybridisation analysis.
Conclusions: Our results provide direct evidence that, in some cases, the progression of DCIS to IDC is driven by either i) the selection of non-modal clones that harbour a specific repertoire of genetic aberrations or ii) the acquisition of specific genetic aberrations by cancer cells in the progression from the in situ to invasive stage.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 10, Tuesday Afternoon