Abstract 2046: Analysis of over-expressed chromosomal regions identifies YBX1 oncogene amplification in basal-like breast tumors (2015)

Abstract DNA copy number change (CNC) is frequently seen in breast tumors, is associated with expression in ∼40% of genes, and has been found to involve all chromosomal arms in varying frequencies. The addition of CNC to gene expression information can improve the accuracy of prognostic predictions, as has been demonstrated by ERBB2 amplification in this tumor type. We wished to determine the clinical correlates of over-expressed chromosomal regions, and whether analysis of these regions can identify driver genes promoting over-expression via CNC. Affymetrix U133 microarray data were assembled from primary breast tumors of 940 women. Over-expressed chromosomal regions were identified utilising a modification of the MicroArray Chromosome Analysis Tool (MACAT) and the DNAcopy program in the R statistical framework. Where regions of elevated expression were conserved between several tumors, smoothed RNA abundance was analysed against chromosomal position to identify genes of recurrent RNA over-expression. By examining several tumors on a whole genome-level using Nimblegen 4.2M tiling arrayCGH analysis and also by quantitative PCR, regional over-expression was confirmed as being a result of DNA CNC. 41 distinct over-expressed chromosomal regions were identified, most frequently observed on chromosomes 1, 8, 11 and 17. Patients with breast tumors containing any significantly over-expressed chromosome region had significantly shorter disease-free survival times (Cox proportional hazard model p = 1×10-6), and shared common clinical characteristics such as high grade and HER2 enriched or basal-like molecular phenotype. Over-expression of region 1p34 containing the YBX1 gene was observed in twelve breast tumors (1.3% of all tumors, 8-9% of basal-like breast tumours, and 70.6% of tumors with chromosome 1 regional over-expression). Disease free survival (DFS) of these twelve patients was significantly shorter than the DFS of all other patients (log rank test p = 4×10-5). In six tumors in which this region was over-expressed at the RNA level we found the YBX1 gene had estimated DNA copy number ≥ 6. YBX1 gene amplification is present across a wide variety of tumor types collected and analysed by TCGA. Approximately 1.7% of tumours within TCGA invasive breast cancer cohort contained this amplification, however the tumor types with highest proportion of YBX1 amplification were ovarian serous cystadenocarcinoma, bladder urothelial carcinoma, pancreatic adenocarcinoma, and sarcoma, with 8.4%, 5%, 1.8% and 1.1% of samples in each tumour group having YBX1 gene amplification respectively. We identify conserved patterns of over-expression of the RNAs encoded by 41 specific chromosomal regions in breast tumors. These include over-expressed regions strongly associated with poor patient prognosis, and the previously undescribed amplification and over-expression of the YBX1 gene on chromosome 1. Citation Format: Abbey Jebb, Sandra Fitzgerald, Sheridan Wilson, Annette Lasham, Cristin Print. Analysis of over-expressed chromosomal regions identifies YBX1 oncogene amplification in basal-like breast tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2046. doi:10.1158/1538-7445.AM2015-2046