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Research Articles

Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations

Franck Tirode, Didier Surdez, Xiaotu Ma, Matthew Parker, Marie Cécile Le Deley, Armita Bahrami, Zhaojie Zhang, Eve Lapouble, Sandrine Grossetête-Lalami, Michael Rusch, Stéphanie Reynaud, Thomas Rio-Frio, Erin Hedlund, Gang Wu, Xiang Chen, Gaelle Pierron, Odile Oberlin, Sakina Zaidi, Gordon Lemmon, Pankaj Gupta, Bhavin Vadodaria, John Easton, Marta Gut, Li Ding, Elaine R. Mardis, Richard K. Wilson, Sheila Shurtleff, Valérie Laurence, Jean Michon, Perrine Marec-Bérard, Ivo Gut, James Downing, Michael Dyer, Jinghui Zhang and Olivier Delattre
Franck Tirode
1INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France.
2Centre de Recherche, Institut Curie, Paris, France.
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Didier Surdez
1INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France.
2Centre de Recherche, Institut Curie, Paris, France.
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Xiaotu Ma
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Matthew Parker
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Marie Cécile Le Deley
4Departement d'Epidémiologie et de Biostatistiques, Gustave Roussy, Villejuif, France.
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Armita Bahrami
5Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Zhaojie Zhang
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Eve Lapouble
6Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
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Sandrine Grossetête-Lalami
1INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France.
2Centre de Recherche, Institut Curie, Paris, France.
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Michael Rusch
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Stéphanie Reynaud
6Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
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Thomas Rio-Frio
2Centre de Recherche, Institut Curie, Paris, France.
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Erin Hedlund
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Gang Wu
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Xiang Chen
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Gaelle Pierron
6Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
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Odile Oberlin
7Departement de Pédiatrie, Gustave Roussy, Villejuif, France.
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Sakina Zaidi
1INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France.
2Centre de Recherche, Institut Curie, Paris, France.
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Gordon Lemmon
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Pankaj Gupta
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Bhavin Vadodaria
8The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
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John Easton
8The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Marta Gut
9Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
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Li Ding
10Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
11Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
12Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
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Elaine R. Mardis
10Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
11Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
12Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
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Richard K. Wilson
10Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
11Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
12Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
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Sheila Shurtleff
5Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Valérie Laurence
13Département d'Oncologie Medicale, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
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Jean Michon
14Département d'Oncologie Pediatrique, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
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Perrine Marec-Bérard
15Institute for Paediatric Haematology and Oncology, Leon Bérard Cancer Centre, University of Lyon, Lyon, France.
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Ivo Gut
9Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
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James Downing
8The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
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Michael Dyer
16Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee.
17Howard Hughes Medical Institute, Chevy Chase, Maryland.
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Jinghui Zhang
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
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  • For correspondence: olivier.delattre@curie.fr jinghui.zhang@stjude.org
Olivier Delattre
1INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France.
2Centre de Recherche, Institut Curie, Paris, France.
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  • For correspondence: olivier.delattre@curie.fr jinghui.zhang@stjude.org
DOI: 10.1158/2159-8290.CD-14-0622 Published November 2014
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Abstract

Ewing sarcoma is a primary bone tumor initiated by EWSR1–ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.

Significance: Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers. Cancer Discov; 4(11); 1342–53. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1243

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received June 16, 2014.
  • Revision received September 4, 2014.
  • Accepted September 5, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Discovery: 4 (11)
November 2014
Volume 4, Issue 11
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Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
Franck Tirode, Didier Surdez, Xiaotu Ma, Matthew Parker, Marie Cécile Le Deley, Armita Bahrami, Zhaojie Zhang, Eve Lapouble, Sandrine Grossetête-Lalami, Michael Rusch, Stéphanie Reynaud, Thomas Rio-Frio, Erin Hedlund, Gang Wu, Xiang Chen, Gaelle Pierron, Odile Oberlin, Sakina Zaidi, Gordon Lemmon, Pankaj Gupta, Bhavin Vadodaria, John Easton, Marta Gut, Li Ding, Elaine R. Mardis, Richard K. Wilson, Sheila Shurtleff, Valérie Laurence, Jean Michon, Perrine Marec-Bérard, Ivo Gut, James Downing, Michael Dyer, Jinghui Zhang and Olivier Delattre for the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project and the International Cancer Genome Consortium
Cancer Discov November 1 2014 (4) (11) 1342-1353; DOI: 10.1158/2159-8290.CD-14-0622

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Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
Franck Tirode, Didier Surdez, Xiaotu Ma, Matthew Parker, Marie Cécile Le Deley, Armita Bahrami, Zhaojie Zhang, Eve Lapouble, Sandrine Grossetête-Lalami, Michael Rusch, Stéphanie Reynaud, Thomas Rio-Frio, Erin Hedlund, Gang Wu, Xiang Chen, Gaelle Pierron, Odile Oberlin, Sakina Zaidi, Gordon Lemmon, Pankaj Gupta, Bhavin Vadodaria, John Easton, Marta Gut, Li Ding, Elaine R. Mardis, Richard K. Wilson, Sheila Shurtleff, Valérie Laurence, Jean Michon, Perrine Marec-Bérard, Ivo Gut, James Downing, Michael Dyer, Jinghui Zhang and Olivier Delattre for the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project and the International Cancer Genome Consortium
Cancer Discov November 1 2014 (4) (11) 1342-1353; DOI: 10.1158/2159-8290.CD-14-0622
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