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Nat Med. 2017 Mar;23(3):386-395. doi: 10.1038/nm.4273. Epub 2017 Jan 30.

DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Institut Curie, PSL Research University, Service de Genetique, Pole de Medecine Diagnostique et Theranostique, Unité de Génétique Somatique, Paris, France.
3
Institut Curie, PSL Research University, INSERM, U830, Paris, France.
4
Institut Curie, PSL Research University, Service de Pathologie, Pole de Medecine Diagnostique et Theranostique, Paris, France.
5
Service d'Anatomie et de Cytologie Pathologiques, Hopitaux de Brabois, Hopital d'Adultes, Nancy, France.
6
Centre de Pathologie du Pôle Est, Hopitaux de Lyon, Lyon, France.
7
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
8
St. Anna Children's Hospital, St. Anna Kinderspital, Vienna, Austria.
9
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
10
Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla, Seville, Spain.
11
Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
12
Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University, Salzburg, Austria.
13
Institute for Experimental and Clinical Cell Therapy, Paracelsus Medical University, Salzburg, Austria.
14
Division of Biomedical Research, Medical University of Graz, Graz, Austria.
15
Institute of Pathology, Medical University of Graz, Graz, Austria.
16
Organizational Unit of Research Infrastructure, Biobank Graz, Medical University of Graz, Graz, Austria.
17
Department of Orthopedic Surgery, Medical University of Graz, Graz, Austria.
18
Service d'Anatomie et de Cytologie Pathologiques, Hôpital Universitaire Trousseau, Tours, France.
19
Gustave Roussy, Département de Pathologie, Villejuif, France.
20
Institut Curie, PSL Research University, Departement d'Oncologie Pédiatrique Adolescent Jeunes Adultes, Paris, France.
21
Department of Orthopedics, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
22
University Hospital Münster, Department of Pediatrics and Pediatric Hematology and Oncology, Münster, Germany.
23
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
24
Max Planck Institute for Informatics, Saarland Informatics Campus, Saarbrücken, Germany.
25
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.

Abstract

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

PMID:
28134926
PMCID:
PMC5951283
DOI:
10.1038/nm.4273
[Indexed for MEDLINE]
Free PMC Article

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