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; Thomas G.P. Grünewald

doi:10.1038/s41467-019-12071-2

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 LiLaura Romero-Pérez, Frank Westermann, Wolfgang Hartmann, Uta Dirksen, Melissa Gymrek, Nathaniel D. Anderson, Adam Shlien, Barak Rotblat, Thomas Kirchner, Olivier Delattre, Thomas G.P. Grünewald

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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.

Original language	English
Article number	4128
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12071-2
State	Published - 1 Dec 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Musa, J., Cidre-Aranaz, F., Aynaud, M. M., Orth, M. F., Knott, M. M. L., Mirabeau, O., Mazor, G., Varon, M., Hölting, T. L. B., Grossetête, S., Gartlgruber, M., Surdez, D., Gerke, J. S., Ohmura, S., Marchetto, A., Dallmayer, M., Baldauf, M. C., Stein, S., Sannino, G., ... Grünewald, T. G. P. (2019). Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes. Nature Communications, 10(1), Article 4128. https://doi.org/10.1038/s41467-019-12071-2

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title = "Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes",

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.",

author = "Julian Musa and Florencia Cidre-Aranaz and Aynaud, {Marie Ming} and Orth, {Martin F.} and Knott, {Maximilian M.L.} and Olivier Mirabeau and Gal Mazor and Mor Varon and H{\"o}lting, {Tilman L.B.} and Sandrine Grosset{\^e}te and Moritz Gartlgruber and Didier Surdez and Gerke, {Julia S.} and Shunya Ohmura and Aruna Marchetto and Marlene Dallmayer and Baldauf, {Michaela C.} and Stefanie Stein and Giuseppina Sannino and Jing Li and Laura Romero-P{\'e}rez and Frank Westermann and Wolfgang Hartmann and Uta Dirksen and Melissa Gymrek and Anderson, {Nathaniel D.} and Adam Shlien and Barak Rotblat and Thomas Kirchner and Olivier Delattre and Gr{\"u}newald, {Thomas G.P.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-12071-2",

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Musa, J, Cidre-Aranaz, F, Aynaud, MM, Orth, MF, Knott, MML, Mirabeau, O, Mazor, G, Varon, M, Hölting, TLB, Grossetête, S, Gartlgruber, M, Surdez, D, Gerke, JS, Ohmura, S, Marchetto, A, Dallmayer, M, Baldauf, MC, Stein, S, Sannino, G, Li, J, Romero-Pérez, L, Westermann, F, Hartmann, W, Dirksen, U, Gymrek, M, Anderson, ND, Shlien, A, Rotblat, B, Kirchner, T, Delattre, O & Grünewald, TGP 2019, 'Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes', Nature Communications, vol. 10, no. 1, 4128. https://doi.org/10.1038/s41467-019-12071-2

TY - JOUR

T1 - Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

AU - Musa, Julian

AU - Cidre-Aranaz, Florencia

AU - Aynaud, Marie Ming

AU - Orth, Martin F.

AU - Knott, Maximilian M.L.

AU - Mirabeau, Olivier

AU - Mazor, Gal

AU - Varon, Mor

AU - Hölting, Tilman L.B.

AU - Grossetête, Sandrine

AU - Gartlgruber, Moritz

AU - Surdez, Didier

AU - Gerke, Julia S.

AU - Ohmura, Shunya

AU - Marchetto, Aruna

AU - Dallmayer, Marlene

AU - Baldauf, Michaela C.

AU - Stein, Stefanie

AU - Sannino, Giuseppina

AU - Li, Jing

AU - Romero-Pérez, Laura

AU - Westermann, Frank

AU - Hartmann, Wolfgang

AU - Dirksen, Uta

AU - Gymrek, Melissa

AU - Anderson, Nathaniel D.

AU - Shlien, Adam

AU - Rotblat, Barak

AU - Kirchner, Thomas

AU - Delattre, Olivier

AU - Grünewald, Thomas G.P.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-019-12071-2

DO - 10.1038/s41467-019-12071-2

M3 - Article

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AN - SCOPUS:85072098155

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4128

ER -

Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

Abstract

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