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DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma
2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Nathan C Sheffield1,26, Gaelle Pierron2, Johanna Klughammer1, Paul Datlinger1, Andreas Schnegger1, Michael Schuster1, Johanna Hadler1, Didier Surdez3, Delphine Guillemot2, Eve Lapouble2, Paul Freneaux4, Jacqueline Champigneulle5, Raymonde Bouvier6, Diana Walder7, Ingeborg M Ambros7, Caroline Hutter8,9,Eva Sorz7, Ana T Amaral10, Enrique de lava10, Katharina Schallmoser11,12, Dirk Strunk11,13, Beate Rinner14, Bernadette Liegl-Atzwanger15, Berthold Huppertz16, Andreas Leithner17, Gonzague de Pinieux18, Philippe Terrier19, Valrie Laurence2,20, Jean Michon20, Ruth Ladenstein79, Wolfgang Holter79, Reinhard Windhager21, Uta Dirksen22, Peter F Ambros7,9, Olivier Delattre2,3,27, Heinrich Kovar7,9,27, Christoph Bock1,2325,27 & Eleni M Tomazou7,27
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.
Ewing sarcoma (EwS) is a developmental cancer defined and diagnosed by the presence of the EWS-FLI1 fusion oncogene1,2. Despite this shared molecular basis, the clinical presentation and disease courses of patients with EwS vary35. This heterogeneity is not reflected by the genetics of EwS, which is characterized by few somatic mutations6 and only three genes with recurrent genetic lesions (CDKN2A, STAG2 and TP53)79. We hypothesized that the observed clinical heterogeneity might coincide with widespread epigenetic heterogeneity, given that two recent studies established the relevance of epigenetics in EwS by
identifying a direct...