title: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.affiliation: INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Surdez
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Matthew
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authors.lastname: Parker
authors.affiliation: Departement d'Epidémiologie et de Biostatistiques, Gustave Roussy, Villejuif, France.
authors.forename: Marie Cécile
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Armita
authors.initials: A
authors.lastname: Bahrami
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
authors.forename: Eve
authors.initials: E
authors.lastname: Lapouble
authors.affiliation: INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Grossetête-Lalami
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Michael
authors.initials: M
authors.lastname: Rusch
authors.affiliation: Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Reynaud
authors.affiliation: Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rio-Frio
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Erin
authors.initials: E
authors.lastname: Hedlund
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Xiang
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authors.lastname: Chen
authors.affiliation: Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
authors.forename: Gaelle
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authors.lastname: Pierron
authors.affiliation: Departement de Pédiatrie, Gustave Roussy, Villejuif, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Oberlin
authors.affiliation: INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Sakina
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Gordon
authors.initials: G
authors.lastname: Lemmon
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.affiliation: The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Bhavin
authors.initials: B
authors.lastname: Vadodaria
authors.affiliation: The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Genetics, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Department of Medicine, The Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.affiliation: Département d'Oncologie Medicale, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Laurence
authors.affiliation: Département d'Oncologie Pediatrique, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
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authors.lastname: Michon
authors.affiliation: Institute for Paediatric Haematology and Oncology, Leon Bérard Cancer Centre, University of Lyon, Lyon, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Marec-Bérard
authors.affiliation: Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
authors.forename: Ivo
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authors.lastname: Gut
authors.affiliation: The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: James
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authors.lastname: Downing
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Dyer
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee. olivier.delattre@curie.fr jinghui.zhang@stjude.org.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France. olivier.delattre@curie.fr jinghui.zhang@stjude.org.
authors.forename: Olivier
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authors.lastname: Delattre
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D023281:Genomics; D006801:Humans; D009154:Mutation; D011379:Prognosis; D012512:Sarcoma, Ewing / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C508565:STAG2 protein, human; D000097722:Cohesins; C495901:TP53 protein, human