Microarray CGH Analysis Reveals Genetic Heterogeneity between Distinct Components of Metaplastic Breast Carcinomas
FC Geyer, D de Biase, B Weigelt, MBK Lambros, A Mackay, K Fenwick, N Tamber, A Ashworth, JS Reis-Filho. ICR, London, United Kingdom; Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley
Background: It has been suggested that breast cancer may be composed of multiple populations of sub-modal clones harbouring the same initiating genetic lesions followed by the acquisition of additional divergent genetic hits. We analysed the genome-wide genetic features of distinct components of metaplastic breast carcinomas (MBCs) to determine whether these components would harbour divergent genetic aberrations.
Design: The distinct components of three carcinomas with heterologous elements (chondroid, spindle and/or epithelial), one biphasic spindle cell carcinoma (spindle and ductal) and one adenosquamous carcinoma (squamous and lobular) were microdissected. DNA was extracted and subjected to microarray comparative genomic hybridisation analysis using a 32K tiling path bacterial artificial chromosome array platform, which has a resolution of 50kb. Representative sections of each case were subjected to immunohistochemistry with antibodies against oestrogen (ER) and progesterone (PR) receptors, HER2, epidermal growth factor receptor (EGFR), cytokeratins (Cks) 5/6 and 14.
Results: The three carcinomas with heterologous elements lacked ER, PR and HER2 expression and expressed Ck 5/6 and/ or Ck14 and/ or EGFR. At genetic level, the components of these lesions displayed identical genetic profiles. The biphasic spindle cell carcinoma lacked ER and PR, and expressed HER2 2+ and basal markers. The components of this case harboured similar gains and losses and amplification of 9p23 and 17q11.2 (HER2); however, only the spindle cell component displayed amplification of 3q24 (ZIC1), 5p15 (TGAT), 9p24 (GLIS3), 10q21 (CDK1, EGR2) and 15q23 (PKM2), whereas only the epithelial component harboured amplification of 8p11.2 (MYST3), 12q14 (CDK4, SAS and GLI1), 15q26 and 17q23 (CAS3, TBX2, TBX4). In the adenosquamous carcinoma the lobular component was positive for ER and PR, and negative for HER2 and basal markers; whereas the squamous component lacked ER, PR and HER2 and expressed basal Cks. Only the squamous component harboured amplification of 7p11.2 (EGFR) and displayed overexpression of EGFR 3+.
Conclusions: Our results provide evidence that in some MBCs, morphological intra-tumour heterogeneity can be ascribed to divergent genetic aberrations, with specific high level amplifications of regions encompassing oncogenes known to play a role in breast cancer.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 29, Monday Morning