RT Journal Article
T1 DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.
A1 Sheffield, Nathan C
A1 Pierron, Gaelle
A1 Klughammer, Johanna
A1 Datlinger, Paul
A1 Schönegger, Andreas
A1 Schuster, Michael
A1 Hadler, Johanna
A1 Surdez, Didier
A1 Guillemot, Delphine
A1 Lapouble, Eve
A1 Freneaux, Paul
A1 Champigneulle, Jacqueline
A1 Bouvier, Raymonde
A1 Walder, Diana
A1 Ambros, Ingeborg M
A1 Hutter, Caroline
A1 Sorz, Eva
A1 Amaral, Ana T
A1 de Álava, Enrique
A1 Schallmoser, Katharina
A1 Strunk, Dirk
A1 Rinner, Beate
A1 Liegl-Atzwanger, Bernadette
A1 Huppertz, Berthold
A1 Leithner, Andreas
A1 de Pinieux, Gonzague
A1 Terrier, Philippe
A1 Laurence, Valérie
A1 Michon, Jean
A1 Ladenstein, Ruth
A1 Holter, Wolfgang
A1 Windhager, Reinhard
A1 Dirksen, Uta
A1 Ambros, Peter F
A1 Delattre, Olivier
A1 Kovar, Heinrich
A1 Bock, Christoph
A1 Tomazou, Eleni M
AB 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.
YR 2017
FD 2017-01-30
LK http://hdl.handle.net/10668/10818
UL http://hdl.handle.net/10668/10818
LA en
DS RISalud
RD Apr 7, 2025