Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
Journal Paper/Review - Sep 11, 2019
Musa Julian, 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, Baldauf Michaela, Dallmayer Marlene, Marchetto Aruna, Cidre-Aranaz Florencia, Aynaud Marie-Ming, Orth Martin F, Knott Maximilian M L, Mirabeau Olivier, Mazor Gal, Varon Mor, Hölting Tilman L B, Grossetête Sandrine, Gartlgruber Moritz, Surdez Didier, Gerke Julia S, Ohmura Shunya, Grünewald Thomas G P
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.