DOI: 10.1101/506659Dec 27, 2018Paper

Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer

BioRxiv : the Preprint Server for Biology
Julian MusaThomas G. P. Grunewald

Abstract

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...Continue Reading

Related Concepts

Biological Markers
Malignant Neoplasms
Cell Survival
DNA
Pharmaceutical Preparations
Genome
Germ Line
Neoplasms
Oncogenes
RNA

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