Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-12071-2
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Funding
- Max-Eder program of the German Cancer Aid [70112257]
- Verein zur Forderung von Wissenschaft und Forschung an der Medizinischen Fakultat der LMU Munchen (WiFoMed)
- LMU Munich's Institutional Strategy LMUexcellent
- Walter Schulz Foundation
- Wilhelm Sander-Foundation [2016.167.1]
- Friedrich-Baur foundation
- Matthias-Lackas foundation
- Dr. Leopold und Carmen Ellinger foundation
- Gert & Susanna Mayer foundation
- Dr. Rolf M. Schwiete foundation
- Deutsche Forschungsgemeinschaft [DFG 391665916]
- German Cancer Aid [111886]
- China Scholarship Council (CSC)
- Kind-Philipp-Stiftung
- Deutsche Stiftung fur Junge Erwachsene mit Krebs
- German Cancer Aid
- German National Academic Foundation
- Max Weber-Program of the State of Bavaria
- ITMO Cancer SysBio program (MOSAIC project) [Nb bio 2014-2]
- European PROVABES project [ERA-649 NET TRANSCAN JTC-2011]
- European ASSET project [FP7-HEALTH-2010-259348]
- Mehr LEBEN fur krebskranke Kinder -Bettina-Brau-Stiftung
- Rudolf und Brigitte Zenner Stiftung
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Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancerlike DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine.
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