The Molecular Underpinning of Lobular Histological Growth Pattern: A Genome-Wide Transcriptomic Analysis of Invasive Lobular Carcinomas and Grade- and Molecular Subtype-Matched Invasive Ductal Carcinomas of No Special Type
B Weigelt, FC Geyer, R Natrajan, MA Lopez-Garcia, AS Ahmad, K Savage, B Kreike, JS Reis-Filho. The Netherlands Cancer Institute, Amsterdam, Netherlands; ICR, London, United Kingdom
Background: The aims of this study were to determine the transcriptomic characteristics of lobular carcinomas (ILCs) and to define the genome-wide transcriptomic differences between classic ILCs and pleomorphic lobular carcinomas (PLCs).
Design: To define the transcriptomic characteristics of ILCs, minimising the impact of histological grade and molecular subtype on the analysis, we subjected a series of ILCs, including classic and pleomorphic variants, and grade- and molecular subtype-matched invasive ductal carcinomas (IDCs) to genome-wide gene expression profiling using oligonucleotide microarrays. Validation of selected genes identified as differentially expressed between ILCs and IDCs and between ILCs and PLCs was performed in an independent cohort of grade- and molecular subtype-matched ILCs and IDCs using real time RT-PCR.
Results: Hierarchical clustering analysis demonstrated that ILCs formed a separate cluster and a supervised analysis revealed that 5.8% of the transcriptionally regulated genes were significantly differentially expressed in ILCs compared to grade- and molecular subtype-matched IDCs. ILCs displayed down-regulation of E-cadherin and of genes related to actin cytoskeleton remodelling, protein ubiquitin, DNA repair, cell adhesion, TGF-beta signalling, and upregulation of transcription factors/ immediate early genes, lipid/ prostaglandin biosynthesis genes, and cell migration-associated genes. Supervised analysis of classic ILCs and PLCs demonstrated that <0.1% of genes were significantly differentially expressed between these tumour subtypes. Quantitative RT-PCR analysis of the independent validation cohort confirmed that ANKRD28 and AFF1 were significantly expressed at higher levels in ILCs than in grade- and molecular subtype-matched IDCs and that HIF1A was expressed at higher levels in PLCs than in ILCs.
Conclusions: Our results demonstrate that ILCs differ from grade- and molecular subtype-matched IDCs in the expression of genes related to cell adhesion, cell-to-cell signalling and actin cytoskeleton signalling. Classic ILCs and PLCs are remarkably similar at the molecular level and should be considered as part of a spectrum of lesions.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 48, Wednesday Morning