1. Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes.
- Author
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Musa, Julian, Cidre-Aranaz, Florencia, Aynaud, Marie-Ming, Orth, Martin F, Knott, Maximilian ML, Mirabeau, Olivier, Mazor, Gal, Varon, Mor, Hölting, Tilman LB, Grossetête, Sandrine, Gartlgruber, Moritz, Surdez, Didier, Gerke, Julia S, Ohmura, Shunya, Marchetto, Aruna, Dallmayer, Marlene, Baldauf, Michaela C, Stein, Stefanie, Sannino, Giuseppina, Li, Jing, Romero-Pérez, Laura, Westermann, Frank, Hartmann, Wolfgang, Dirksen, Uta, Gymrek, Melissa, Anderson, Nathaniel D, Shlien, Adam, Rotblat, Barak, Kirchner, Thomas, Delattre, Olivier, and Grünewald, Thomas GP
- Subjects
Cell Line ,Tumor ,Animals ,Humans ,Mice ,Neoplasms ,Cell Cycle Proteins ,Trans-Activators ,Neoplasm Proteins ,Oncogene Proteins ,Fusion ,Treatment Outcome ,Cell Proliferation ,Cell Survival ,Gene Expression Regulation ,Neoplastic ,Up-Regulation ,Microsatellite Repeats ,Phenotype ,Germ-Line Mutation ,Polymorphism ,Genetic ,Cyclin-Dependent Kinase 2 ,HEK293 Cells ,Cell Line ,Tumor ,Gene Expression Regulation ,Neoplastic ,Oncogene Proteins ,Fusion ,Polymorphism ,Genetic - 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.
- Published
- 2019