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.
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Acknowledgements
We thank to the Spanish Society of Pediatric Oncology (SEOP) and particularly to Drs Ma I Pintor, J Durán, A Jiménez, A Navajas, JL Vivanco, T Acha, A Cantalejo, P Galarón, A Muñoz, M Torrent, N Pardo, A Carboné, C Calvo, A Nieto, M Guibelalde and J Molina for providing us with the tumour samples and clinical data used in this study.We also thank Ministerio de Educación y Ciencia (SAF2003-01068, SAF2005-04340 and SAF2006-07586), Ministerio de Sanidad (G03/089, C03/10, PI050197), Fundación Inocente Inocente and Fundación Enriqueta Villavecchia, for their financial support. BIF has a Marie Curie PhD Earyl Stage Research Training Fellowship. J Carrillo is supported for a postdoctoral contract from the FGUAM.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Ferreira, B., Alonso, J., Carrillo, J. et al. Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma. Oncogene 27, 2084–2090 (2008). https://doi.org/10.1038/sj.onc.1210845
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DOI: https://doi.org/10.1038/sj.onc.1210845
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