Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Sheffield, NC; Pierron, G; Klughammer, J; Datlinger, P; Schönegger, A; Schuster, M; Hadler, J; Surdez, D; Guillemot, D; Lapouble, E; Freneaux, P; Champigneulle, J; Bouvier, R; Walder, D; Ambros, IM; Hutter, C; Sorz, E; Amaral, AT; de Álava, E; Schallmoser, K; Strunk, D; Rinner, B; Liegl-Atzwanger, B; Huppertz, B; Leithner, A; de Pinieux, G; Terrier, P; Laurence, V; Michon, J; Ladenstein, R; Holter, W; Windhager, R; Dirksen, U; Ambros, PF; Delattre, O; Kovar, H; Bock, C; Tomazou, EM.
DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma.
Nat Med. 2017; 23(3):386-395
Doi: 10.1038/nm.4273
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- Co-Autor*innen der Med Uni Graz
- Huppertz Berthold
- Leithner Andreas
- Liegl-Atzwanger Bernadette
- Rinner Beate
- Schallmoser Katharina
- Windhager Reinhard
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adolescent -
- Adult -
- Bone Neoplasms - genetics
- Cell Line, Tumor -
- Child -
- Child, Preschool -
- DNA Methylation - genetics
- Epigenesis, Genetic -
- Female -
- Gene Expression Regulation, Neoplastic -
- Genetic Heterogeneity -
- Humans -
- Male -
- Middle Aged -
- Oncogene Proteins, Fusion - genetics
- Promoter Regions, Genetic - genetics
- Proto-Oncogene Protein c-fli-1 - genetics
- RNA-Binding Protein EWS - genetics
- Sarcoma, Ewing - genetics
- Young Adult -