title: Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas.
abstract: Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Maryou B K
authors.initials: MB
authors.lastname: Lambros
authors.forename: Dario
authors.initials: D
authors.lastname: de Biase
authors.forename: Radost
authors.initials: R
authors.lastname: Vatcheva
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D019143:Evolution, Molecular; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D008679:Metaplasia / Q000235:genetics; D042282:Microdissection / Q000379:methods; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods