1. ¹Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), and CIBER on Rare Diseases (CIBERER), Madrid, Spain
2. ²Departamento de Biología Molecular y Celular del Cáncer, Instituto de Investigaciones Biomédicas 'A. Sols' (CSIC-UAM), Madrid, Spain
3. ³Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), Porto, Portugal
4. ⁴Fundación Biomédica del CHUVI, Hospital do Rebullón, Vigo, Pontevedra, Spain
5. ⁵Unidad de Bioinformática, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
6. ⁶Unidad Oncohematología Infantil, Hospital Infantil La Paz, Madrid, Spain

Correspondence: Dr JC Cigudosa, Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), 3 C/Melchor Fernández Almagro, Madrid 28089, Spain. E-mail: jccigudosa@cnio.es; Dr J Alonso, Departamento de Biología Molecular y Celular del Cáncer, Instituto de Investigaciones Biomédicas 'A Sols', CSIC-UAM, C/ Arturo Duperier 4, Madrid 28029, Spain. E-mail: jalonso@iib.uam.es

⁷These two authors contributed equally to this work.

Received 12 March 2007; Revised 4 July 2007; Accepted 10 September 2007; Published online 22 October 2007.

Abstract

Ewing's sarcoma (ES) is characterized by specific chromosome translocations, the most common being t(11;22)(q24;q12). Additionally, other type of genetic abnormalities may occur and be relevant for explaining the variable tumour biology and clinical outcome. We have carried out a high-resolution array CGH and expression profiling on 25 ES tumour samples to characterize the DNA copy number aberrations (CNA) occurring in these tumours and determine their association with gene-expression profiles and clinical outcome. CNA were observed in 84% of the cases. We observed a median number of three aberrations per case. Besides numerical chromosome changes, smaller aberrations were found and defined at chromosomes 5p, 7q and 9p. All CNA were compiled to define the smallest overlapping regions of imbalance (SORI). A total of 35 SORI were delimited. Bioinformatics analyses were conducted to identify subgroups according to the pattern of genomic instability. Unsupervised and supervised clustering analysis (using SORI as variables) segregated the tumours in two distinct groups: one genomically stable (3 CNA) and other genomically unstable (>3 CNA). The genomic unstable group showed a statistically significant shorter overall survival and was more refractory to chemotherapy. Expression profile analysis revealed significant differences between both groups. Genes related with chromosome segregation, DNA repair pathways and cell-cycle control were upregulated in the genomically unstable group. This report elucidates, for the first time, data about genomic instability in ES, based on CNA and expression profiling, and shows that a genomically unstable group of Ewing's tumours is correlated with a significant poor prognosis.