[288] Identification of Drivers of the 11q13 Amplicon.

Paul Wilkerson, Alan Mackay, Maryou B Lambros, Rachael Natrajan, Hugo Horlings, Marc J van de Vijver, Jorge S Reis-Filho. Institute of Cancer Research, London, United Kingdom; Academic Medical Center, Amsterdam, Netherlands

Background: Amplification of the 11q13-q14 locus occurs in approximately 15% of breast cancers, and has a complex amplicon structure. Potential drivers of this amplicon (i.e. genes whose expression is essential for the survival of cancer cells harbouring their amplification) include GAB2, PAK1, CTTN and CCND1. Previous studies have demonstrated that amplicons may contain more than one driver. Importantly, it has become apparent that amplicon drivers are consistently overexpressed when amplified. We sought to identify the potential drivers of this amplicon by integrating microarray-based comparative genomic hybridisation (aCGH) and gene expression data and to identify models to study the 11q13-q14 amplicon.
Design: 331 invasive ductal carcinomas of no special type (IDC-NSTs) and 46 breast cancer cell lines were profiled using an in-house 32K bacterial artificial chromosome (BAC) aCGH platform. 54 cases with amplification of 11q13-q14 were then examined to define the smallest regions of amplifications (SRAs) in the 11q13-q14 amplicon. Using 3 independent data sets, we integrated aCGH and expression data to define the genes that map to the SRA and are consistently overexpressed when amplified.
Results: Fine mapping of the 11q13-14 amplicon revealed its complexity and demonstrated that 88 genes are recurrently amplified in the SRAs. Out of these genes, 25 were overexpressed when amplified in each independent dataset of primary breast cancers. This list included the known drivers of the 11q13-q14 amplicon (e.g. GAB2, PAK1, CCND1, and CTTN). Sixteen of these genes were common to both tumour data sets and including genes likely to be drivers of specific cores of the 11q13-q14 amplicon, such as CTTN, PAK1, GAB2, ORAOV1 and RSF1. Sixteen breast cancer cell lines harbouring 11q13-q14 amplification were identified in which 39 genes were significantly over-expressed when amplified. Fifteen of these genes were common between the 3 data sets.
Conclusions: We have identified a list of genes consistently overexpressed when amplified that map to the SRAs of the 11q13-q14 amplicon in primary breast cancers, and may constitute potential drivers of this amplicon. We have also characterised the genomic profiles of 16 breast cancer cell lines that can be employed to model this amplicon. These genes will be systematically tested in cell line models using RNA interference screens to determine whether their expression is essential for the survival of cancer cells harbouring their amplification.
Category: Breast

Tuesday, March 1, 2011 1:00 PM

Poster Session IV # 19, Tuesday Afternoon

 

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