Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer
INTRODUCTORY PARAGRAPH Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma (EwS) feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome.Here we demonstrate in the EwS model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response.We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Analysis of paired germline and tumor whole-genome sequencing data revealed that regulatory variability at this locus is inherited via the germline. CRISPR-mediated interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased cell proliferation, cell survival and tumorigenicity of EwS cells. Combined RNA- and ChIP-seq analyses as well as functional experiments and clinical data identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments, high MYBL2 levels sensitized EwS cells for inhibition of its activating cyclin dependent kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine..
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Preprint| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
bioRxiv.org - (2020) vom: 18. Jan. Zur Gesamtaufnahme - year:2020 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Musa, Julian [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/506659 |
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| PPN (Katalog-ID): |
XBI000419680 |
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| 520 | |a INTRODUCTORY PARAGRAPH Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma (EwS) feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome.Here we demonstrate in the EwS model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response.We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Analysis of paired germline and tumor whole-genome sequencing data revealed that regulatory variability at this locus is inherited via the germline. CRISPR-mediated interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased cell proliferation, cell survival and tumorigenicity of EwS cells. Combined RNA- and ChIP-seq analyses as well as functional experiments and clinical data identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments, high MYBL2 levels sensitized EwS cells for inhibition of its activating cyclin dependent kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine. | ||
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| 700 | 1 | |a Aynaud, Marie-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Orth, Martin F. |e verfasserin |4 aut | |
| 700 | 1 | |a Mirabeau, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Varon, Mor |e verfasserin |4 aut | |
| 700 | 1 | |a Grossetête, Sandrine |e verfasserin |4 aut | |
| 700 | 1 | |a Surdez, Didier |e verfasserin |4 aut | |
| 700 | 1 | |a Ohmura, Shunya |e verfasserin |4 aut | |
| 700 | 1 | |a Gerke, Julia S. |e verfasserin |4 aut | |
| 700 | 1 | |a Marchetto, Aruna |e verfasserin |4 aut | |
| 700 | 1 | |a Dallmayer, Marlene |e verfasserin |4 aut | |
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| 700 | 1 | |a Gartlgruber, Moritz |e verfasserin |4 aut | |
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| 700 | 1 | |a Hölting, Tilman L. B. |e verfasserin |4 aut | |
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