Comprehensive Genomic and Transcriptomic Analysis of the 11q13 Amplicon in Breast Cancer.

Abstract

Abstract Background: The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event associated with ER positive status but also implicated in resistance to endocrine therapies. Coamplifications of the 11q13 and 8p12 regions are commonly occurring, suggesting a synergy between genes in the amplicons. The present aim was to perform a comprehensive analysis of breast tumours harbouring amplification in the 11q13 region, and identify candidate oncogenes in the amplicon based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 connection was evaluated at the mRNA level, as well as its prognostic significance.Methods/materials: Affymetrix 250K Nsp SNP arrays were used for whole genome screening of DNA copy number changes in 29 breast tumours, assumed to be representative for the majority of 11q13 amplified cases in a patient material consisting of 200 postmenopausal women with stage II breast tumours. To identify regions of significant aberrations at 11q13 and 8p12 across all tumours, the principles of a statistical approach called Genomic Identification of Significant Targets in Cancer (GISTIC) was applied. mRNA expression levels of candidate oncogenes in respective amplicon (RAD9A, RPS6KB2, CCND1, FGF19, PAK1, GAB2 (11q13); EIF4EBP1, PPAPDC1B and FGFR1 (8p12) were evaluated using quantitative real-time PCR.Results: Resulting data revealed three main amplification cores at 11q13, centred on 66.9Mb, 69.1Mb and 77.0Mb. Loss of the distal part of 11q occurred in 97% (28/29) of the cases. With the exception for FGF19, a correlation between mRNA level and gene copy number was seen for all genes included in the study. ER expression was associated with the central 11q13 core, though no significant correlation to mRNA expression of included genes could be stated. Regarding the 8p12/11q13 connection, it was shown that DNA copy number, as well as mRNA-expression levels, significantly correlated between RPS6KB2 (core 66.9Mb, 11q13) and EIF4EBP1/PPAPDC1B (8p12). Amplification at 8p12 was significantly inversely correlated to 17q (HER2) amplification, whereas HER2 protein was significantly negatively correlated to PPAPDC1B mRNA-levels. High expression of RPS6KB2, EIF4EBP1 and FGFR1 was associated with a significant increased risk of distant recurrence in the patient group. Coexpression of RPS6KB2 and EIF4EBP1 was shown to predict a worse patient outcome compared to overexpression of only one of the genes, supporting earlier suggestions of a synergy between the 11q13 and 8p12 amplicons.Conclusions: The present study identifies three main amplification cores at 11q13 in breast tumours, with the most proximal correlated to 8p12 at both the genomic and the transcriptomic level. A clinical significance of RPS6KB2(11q13)/EIF4EBP1(8p12) coexpression/coamplification was indicated, but needs to be evaluated in larger patient cohorts. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5166.