Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes.
Animals
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cyclin-Dependent Kinase 2
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
Germ-Line Mutation
/ genetics
HEK293 Cells
Humans
Mice
Microsatellite Repeats
/ genetics
Neoplasm Proteins
/ metabolism
Neoplasms
/ genetics
Oncogene Proteins, Fusion
/ metabolism
Phenotype
Polymorphism, Genetic
Trans-Activators
Treatment Outcome
Up-Regulation
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 09 2019
11 09 2019
Historique:
received:
15
02
2019
accepted:
16
08
2019
entrez:
13
9
2019
pubmed:
13
9
2019
medline:
24
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31511524
doi: 10.1038/s41467-019-12071-2
pii: 10.1038/s41467-019-12071-2
pmc: PMC6739408
doi:
Substances chimiques
Cell Cycle Proteins
0
EWSR1-FLI1 fusion protein, human
0
MYBL2 protein, human
0
Neoplasm Proteins
0
Oncogene Proteins, Fusion
0
Trans-Activators
0
Cyclin-Dependent Kinase 2
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4128Références
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