Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

Publikation

Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

Wissenschaftlicher Artikel/Review - 11.09.2019

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

Zitation

Musa J, Stein S, Sannino G, Li J, Romero-Pérez L, Westermann F, Hartmann W, Dirksen U, Gymrek M, Anderson N, Shlien A, Rotblat B, Kirchner T, Delattre O, Baldauf M, Dallmayer M, Marchetto A, Cidre-Aranaz F, Aynaud M, Orth M, Knott M, Mirabeau O, Mazor G, Varon M, Hölting T, Grossetête S, Gartlgruber M, Surdez D, Gerke J, Ohmura S, Grünewald T. Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes. Nat Commun 2019; 10:4128.

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

Nat Commun 2019; 10

Veröffentlichungsdatum

11.09.2019

eISSN (Online)

2041-1723

Seiten

4128

Kurzbeschreibung/Zielsetzung

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.