Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma (original) (raw)

• Original Article
• Published: 22 October 2007
• J Alonso2 na1,
• J Carrillo2,
• F Acquadro1,
• C Largo1,
• J Suela1,
• M R Teixeira3,
• N Cerveira3,
• A Molares4,
• G Goméz-López4,5,
• Á Pestaña2,
• A Sastre6,
• P Garcia-Miguel6 &
• …
• J C Cigudosa1 na1

Oncogene volume 27, pages 2084–2090 (2008)Cite this article

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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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References

• Armengol G, Tarkkanen M, Virolainen M, Forus A, Valle J, Bohling T et al. (1997). Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization. Br J Cancer 75: 1403–1409.
  Article CAS PubMed PubMed Central Google Scholar
• Aurias A, Rimbaut C, Buffe D, Zucker JM, Mazabraud A . (1984). Translocation involving chromosome 22 in Ewing's sarcoma. A cytogenetic study of four fresh tumors. Cancer Genet Cytogenet 12: 21–25.
  Article CAS PubMed Google Scholar
• Bandres E, Malumbres R, Escalada A, Cubedo E, Gonzalez I, Honorato B et al. (2005). Gene expression profile of ewing sarcoma cell lines differing in their EWS-FLI1 fusion type. J Pediatr Hematol Oncol 27: 537–542.
  Article PubMed Google Scholar
• Blaveri E, Brewer JL, Roydasgupta R, Fridlyand J, DeVries S, Koppie T et al. (2005). Bladder cancer stage and outcome by array-based comparative genomic hybridization. Clin Cancer Res 11: 7012–7022.
  Article CAS PubMed Google Scholar
• Brisset S, Schleiermacher G, Peter M, Mairal A, Oberlin O, Delattre O et al. (2001). CGH analysis of secondary genetic changes in Ewing tumors: correlation with metastatic disease in a series of 43 cases. Cancer Genet Cytogenet 130: 57–61.
  Article CAS PubMed Google Scholar
• Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M et al. (1992). Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359: 162–165.
  Article CAS PubMed Google Scholar
• Eilers PH, de Menezes RX . (2005). Quantile smoothing of array CGH data. Bioinformatics 21: 1146–1153.
  Article CAS PubMed Google Scholar
• Hattinger CM, Potschger U, Tarkkanen M, Squire J, Zielenska M, Kiuru-Kuhlefelt S et al. (2002). Prognostic impact of chromosomal aberrations in Ewing tumours. Br J Cancer 86: 1763–1769.
  Article CAS PubMed PubMed Central Google Scholar
• Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F et al. (2001). Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7: 673–679.
  Article CAS PubMed PubMed Central Google Scholar
• Kovar H . (1998). Ewing's sarcoma and peripheral primitive neuroectodermal tumors after their genetic union. Curr Opin Oncol 10: 334–342.
  Article CAS PubMed Google Scholar
• Mendiola M, Carrillo J, Garcia E, Lalli E, Hernandez T, de Alava E et al. (2006). The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer 118: 1381–1389.
  Article CAS PubMed Google Scholar
• Mugneret F, Lizard S, Aurias A, Turc-Carel C . (1988). Chromosomes in Ewing's sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 32: 239–245.
  Article CAS PubMed Google Scholar
• Ohali A, Avigad S, Zaizov R, Ophir R, Horn-Saban S, Cohen IJ et al. (2004). Prediction of high risk Ewing's sarcoma by gene expression profiling. Oncogene 23: 8997–9006.
  Article CAS PubMed Google Scholar
• Ozaki T, Paulussen M, Poremba C, Brinkschmidt C, Rerin J, Ahrens S et al. (2001). Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer 32: 164–171.
  Article CAS PubMed Google Scholar
• Pinkel D, Albertson DG . (2005). Comparative genomic hybridization. Annu Rev Genomics Hum Genet 6: 331–354.
  Article CAS PubMed Google Scholar
• Rouveirol C, Stransky N, Hupe P, Rosa PL, Viara E, Barillot E et al. (2006). Computation of recurrent minimal genomic alterations from array-CGH data. Bioinformatics 22: 849–856.
  Article CAS PubMed Google Scholar
• Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. (2005). Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102: 15545–15550.
  Article CAS PubMed Google Scholar
• Thompson PM, Maris JM, Hogarty MD, Seeger RC, Reynolds CP, Brodeur GM et al. (2001). Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res 61: 679–686.
  CAS PubMed Google Scholar
• Ushigome U, Machinami R, Sorensen PH . (2002). Ewing sarcoma/primitive neuroectodermal tumor (PNET). In: Fletcher CDM, Unni KK, Mertens F (eds). Pathology and Genetics of Tumors of Soft Tissue and Bone. Wold Health Organization Classification of Tumors. IARC Press: France. pp 298–300.
  Google Scholar
• Wu W, Dave N, Tseng GC, Richards T, Xing EP, Kaminski N . (2005). Comparison of normalization methods for CodeLink Bioarray data. BMC Bioinformatics 6: 309.
  Article PubMed PubMed Central Google Scholar
• Zielenska M, Zhang ZM, Ng K, Marrano P, Bayani J, Ramirez OC et al. (2001). Acquisition of secondary structural chromosomal changes in pediatric Ewing sarcoma is a probable prognostic factor for tumor response and clinical outcome. Cancer 91: 2156–2164.
  Article CAS PubMed Google Scholar

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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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Author notes

1. J Alonso and J C Cigudosa: These two authors contributed equally to this work.

Authors and Affiliations

1. Molecular Cytogenetics Group, Centro Nacional de Investigaciones Oncológicas (CNIO), and CIBER on Rare Diseases (CIBERER), Madrid, Spain
   B I Ferreira, F Acquadro, C Largo, J Suela & J C Cigudosa
2. Departamento de Biología Molecular y Celular del Cáncer, Instituto de Investigaciones Biomédicas ‘A. Sols’ (CSIC-UAM), Madrid, Spain
   J Alonso, J Carrillo & Á Pestaña
3. Department of Genetics, Portuguese Oncology Institute and Biomedical Sciences Institute (ICBAS), Porto, Portugal
   M R Teixeira & N Cerveira
4. Fundación Biomédica del CHUVI, Hospital do Rebullón, Vigo, Pontevedra, Spain
   A Molares & G Goméz-López
5. Unidad de Bioinformática, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
   G Goméz-López
6. Unidad Oncohematología Infantil, Hospital Infantil La Paz, Madrid, Spain
   A Sastre & P Garcia-Miguel

Authors

1. B I Ferreira
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2. J Alonso
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3. J Carrillo
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4. F Acquadro
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5. C Largo
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6. J Suela
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7. M R Teixeira
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8. N Cerveira
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9. A Molares
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10. G Goméz-López
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11. Á Pestaña
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12. A Sastre
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13. P Garcia-Miguel
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14. J C Cigudosa
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Corresponding authors

Correspondence toJ Alonso or J C Cigudosa.

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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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• Received: 12 March 2007
• Revised: 04 July 2007
• Accepted: 10 September 2007
• Published: 22 October 2007
• Issue Date: 27 March 2008
• DOI: https://doi.org/10.1038/sj.onc.1210845

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