title: The genomic landscape of pediatric Ewing sarcoma.
abstract: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease.
  
  
  CONCLUSIONS
  We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Crompton
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts. Eli and Edythe L. Broad Institute, Cambridge, Massachusetts. Bioinformatics Graduate Program, Boston University, Boston, Massachusetts.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Kurek
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Calicchio
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Adam
authors.initials: A
authors.lastname: Kiezun
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Swapnil S
authors.initials: SS
authors.lastname: Mehta
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Torres
authors.affiliation: Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lavarino
authors.affiliation: Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Suñol
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Mara
authors.initials: M
authors.lastname: Rosenberg
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Sara
authors.initials: S
authors.lastname: Seepo
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Brendan
authors.initials: B
authors.lastname: Blumenstiel
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: DeFelice
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
authors.forename: Ivan
authors.initials: I
authors.lastname: Imaz-Rosshandler
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
authors.forename: Angela
authors.initials: A
authors.lastname: Schwarz-Cruz Y Celis
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts. Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Eli and Edythe L. Broad Institute, Cambridge, Massachusetts. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts. Eli and Edythe L. Broad Institute, Cambridge, Massachusetts. kimberly_stegmaier@dfci.harvard.edu.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D023281:Genomics; D006801:Humans; D008297:Male; D009154:Mutation; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C508565:STAG2 protein, human; D000097722:Cohesins