Journal
NATURE MEDICINE
Volume 23, Issue 3, Pages 386-395Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4273
Keywords
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Funding
- Austrian National Bank's Jubilaumsfonds [15714]
- INSERM within the framework of the International Cancer Genome Consortium program
- Ligue Nationale Contre Le Cancer (Equipe labellisee)
- Societe Francaise des Cancers de l'Enfant
- European Union [602856, 282510, 01KT1310, 259348, 668724]
- Human Frontier Science Program [LT000211/2014]
- DOC Fellowship of the Austrian Academy of Sciences
- Institut Curie-SIRIC (Site de Recherche Integree en Cancerologie) program
- Ministry of Economy and Competitiveness of Spain-FEDER grants (CBJERONC) [RD12/0036/0017, PI14/01466]
- Maria Garcia-Estrada
- CRIS contra el Cancer Foundations
- Pablo Ugarte Association
- New Frontiers Group award of the Austrian Academy of Sciences
- European Research Council (ERC) Starting Grant (European Union's Horizon research and innovation program) [679146]
- Austrian Science Fund (FWF) [M1448-B13, V506-B28]
- Austrian Science Fund (FWF) [M1448, I1225, V506] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [V 506, M 1448, I 1225] Funding Source: researchfish
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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.
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