Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

Julian Musa, Florencia Cidre-Aranaz, Marie-Ming Aynaud, Martin F. Orth, Maximilian M. L. Knott, Olivier Mirabeau, Gal Mazor, Mor Varon, Tilman L. B. Hölting, Sandrine Grossetête, Moritz Gartlgruber, Didier Surdez, Julia S. Gerke, Shunya Ohmura, Aruna Marchetto, Marlene Dallmayer, Michaela C. Baldauf, Stefanie Stein, Giuseppina Sannino, Jing Li, Laura Romero-Pérez, Frank Westermann, Wolfgang Hartmann, Uta Dirksen, Melissa Gymrek, Nathaniel D. Anderson, Adam Shlien, Barak Rotblat, Thomas Kirchner, Olivier Delattre and Thomas G. P. Grünewald ()
Additional contact information
Julian Musa: Faculty of Medicine, LMU Munich
Florencia Cidre-Aranaz: Faculty of Medicine, LMU Munich
Marie-Ming Aynaud: Institut Curie Research Centre
Martin F. Orth: Faculty of Medicine, LMU Munich
Maximilian M. L. Knott: Faculty of Medicine, LMU Munich
Olivier Mirabeau: Institut Curie Research Centre
Gal Mazor: Ben-Gurion University of the Negev
Mor Varon: Ben-Gurion University of the Negev
Tilman L. B. Hölting: Faculty of Medicine, LMU Munich
Sandrine Grossetête: Institut Curie Research Centre
Moritz Gartlgruber: German Cancer Research Center (DKFZ)
Didier Surdez: Institut Curie Research Centre
Julia S. Gerke: Faculty of Medicine, LMU Munich
Shunya Ohmura: Faculty of Medicine, LMU Munich
Aruna Marchetto: Faculty of Medicine, LMU Munich
Marlene Dallmayer: Faculty of Medicine, LMU Munich
Michaela C. Baldauf: Faculty of Medicine, LMU Munich
Stefanie Stein: Faculty of Medicine, LMU Munich
Giuseppina Sannino: Faculty of Medicine, LMU Munich
Jing Li: Faculty of Medicine, LMU Munich
Laura Romero-Pérez: Faculty of Medicine, LMU Munich
Frank Westermann: German Cancer Research Center (DKFZ)
Wolfgang Hartmann: University Hospital of Münster
Uta Dirksen: University Hospital of Essen
Melissa Gymrek: University of California, San Diego
Nathaniel D. Anderson: The Hospital for Sick Children
Adam Shlien: The Hospital for Sick Children
Barak Rotblat: Ben-Gurion University of the Negev
Thomas Kirchner: LMU Munich
Olivier Delattre: Institut Curie Research Centre
Thomas G. P. Grünewald: Faculty of Medicine, LMU Munich

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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 enhancer-like 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.

Date: 2019
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DOI: 10.1038/s41467-019-12071-2

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