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Cancer Discov. 2014 Nov;4(11):1342-53. doi: 10.1158/2159-8290.CD-14-0622. Epub 2014 Sep 15.

Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.

Author information

1
INSERM U830, Laboratory of Genetics and Cancer Biology, Institut Curie, Paris, France. Centre de Recherche, Institut Curie, Paris, France.
2
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
3
Departement d'Epidémiologie et de Biostatistiques, Gustave Roussy, Villejuif, France.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
5
Unité de Génétique Somatique, Centre Hospitalier, Institut Curie, Paris, France.
6
Centre de Recherche, Institut Curie, Paris, France.
7
Departement de Pédiatrie, Gustave Roussy, Villejuif, France.
8
The Pediatric Cancer Genome Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee.
9
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain.
10
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.
11
Département d'Oncologie Medicale, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
12
Département d'Oncologie Pediatrique, Adolescents et Jeunes Adultes, Centre Hospitalier, Institut Curie, Paris, France.
13
Institute for Paediatric Haematology and Oncology, Leon Bérard Cancer Centre, University of Lyon, Lyon, France.
14
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee. Howard Hughes Medical Institute, Chevy Chase, Maryland.
15
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee. olivier.delattre@curie.fr jinghui.zhang@stjude.org.
16
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.

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.

PMID:
25223734
PMCID:
PMC4264969
DOI:
10.1158/2159-8290.CD-14-0622
[Indexed for MEDLINE]
Free PMC Article

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