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Research Articles

The Genomic Landscape of Pediatric Ewing Sarcoma

Brian D. Crompton, Chip Stewart, Amaro Taylor-Weiner, Gabriela Alexe, Kyle C. Kurek, Monica L. Calicchio, Adam Kiezun, Scott L. Carter, Sachet A. Shukla, Swapnil S. Mehta, Aaron R. Thorner, Carmen de Torres, Cinzia Lavarino, Mariona Suñol, Aaron McKenna, Andrey Sivachenko, Kristian Cibulskis, Michael S. Lawrence, Petar Stojanov, Mara Rosenberg, Lauren Ambrogio, Daniel Auclair, Sara Seepo, Brendan Blumenstiel, Matthew DeFelice, Ivan Imaz-Rosshandler, Angela Schwarz-Cruz y Celis, Miguel N. Rivera, Carlos Rodriguez-Galindo, Mark D. Fleming, Todd R. Golub, Gad Getz, Jaume Mora and Kimberly Stegmaier
Brian D. Crompton
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
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Chip Stewart
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Amaro Taylor-Weiner
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Gabriela Alexe
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
3Bioinformatics Graduate Program, Boston University, Boston, Massachusetts.
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Kyle C. Kurek
4Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
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Monica L. Calicchio
4Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
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Adam Kiezun
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Scott L. Carter
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Sachet A. Shukla
5Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Swapnil S. Mehta
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
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Aaron R. Thorner
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
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Carmen de Torres
6Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
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Cinzia Lavarino
6Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
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Mariona Suñol
6Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
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Aaron McKenna
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Andrey Sivachenko
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Kristian Cibulskis
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Michael S. Lawrence
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Petar Stojanov
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Mara Rosenberg
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Lauren Ambrogio
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Daniel Auclair
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Sara Seepo
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Brendan Blumenstiel
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Matthew DeFelice
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Ivan Imaz-Rosshandler
8Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
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Angela Schwarz-Cruz y Celis
8Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
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Miguel N. Rivera
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
9Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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Carlos Rodriguez-Galindo
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
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Mark D. Fleming
4Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
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Todd R. Golub
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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Gad Getz
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
9Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
10Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
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Jaume Mora
6Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
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Kimberly Stegmaier
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.
2Eli and Edythe L. Broad Institute, Cambridge, Massachusetts.
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  • For correspondence: kimberly_stegmaier@dfci.harvard.edu
DOI: 10.1158/2159-8290.CD-13-1037 Published November 2014
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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.

Significance: 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. Cancer Discov; 4(11); 1326–41. ©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/).

  • G. Getz, J. Mora, and K. Stegmaier jointly directed this work.

  • Received December 26, 2013.
  • Revision received August 19, 2014.
  • Accepted August 29, 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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The Genomic Landscape of Pediatric Ewing Sarcoma
Brian D. Crompton, Chip Stewart, Amaro Taylor-Weiner, Gabriela Alexe, Kyle C. Kurek, Monica L. Calicchio, Adam Kiezun, Scott L. Carter, Sachet A. Shukla, Swapnil S. Mehta, Aaron R. Thorner, Carmen de Torres, Cinzia Lavarino, Mariona Suñol, Aaron McKenna, Andrey Sivachenko, Kristian Cibulskis, Michael S. Lawrence, Petar Stojanov, Mara Rosenberg, Lauren Ambrogio, Daniel Auclair, Sara Seepo, Brendan Blumenstiel, Matthew DeFelice, Ivan Imaz-Rosshandler, Angela Schwarz-Cruz y Celis, Miguel N. Rivera, Carlos Rodriguez-Galindo, Mark D. Fleming, Todd R. Golub, Gad Getz, Jaume Mora and Kimberly Stegmaier
Cancer Discov November 1 2014 (4) (11) 1326-1341; DOI: 10.1158/2159-8290.CD-13-1037

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The Genomic Landscape of Pediatric Ewing Sarcoma
Brian D. Crompton, Chip Stewart, Amaro Taylor-Weiner, Gabriela Alexe, Kyle C. Kurek, Monica L. Calicchio, Adam Kiezun, Scott L. Carter, Sachet A. Shukla, Swapnil S. Mehta, Aaron R. Thorner, Carmen de Torres, Cinzia Lavarino, Mariona Suñol, Aaron McKenna, Andrey Sivachenko, Kristian Cibulskis, Michael S. Lawrence, Petar Stojanov, Mara Rosenberg, Lauren Ambrogio, Daniel Auclair, Sara Seepo, Brendan Blumenstiel, Matthew DeFelice, Ivan Imaz-Rosshandler, Angela Schwarz-Cruz y Celis, Miguel N. Rivera, Carlos Rodriguez-Galindo, Mark D. Fleming, Todd R. Golub, Gad Getz, Jaume Mora and Kimberly Stegmaier
Cancer Discov November 1 2014 (4) (11) 1326-1341; DOI: 10.1158/2159-8290.CD-13-1037
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