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.
Highlights
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
Collectively, our discoveries made in an aggressive childhood cancer exemplify how oncogenic cooperation between a cancer driver-mutation and a regulatory germline variant can create a major source of inter-tumor heterogeneity determining clinical outcome and drug response through modulation of a druggable key downstream player (Fig. 4d)
To explore the possibility of such oncogenic cooperation in EwS beyond MYBL2, we analyzed the top five additional hits of our initial screen whose high expression was associated with worse patient overall survival (EXO1, C1ORF112, ESPL1, HJURP, RAD54L; Supplementary Data 3) for the presence of EWSR1FLI1 bound GGAA-microsatellites or ETS-like binding motifs in the vicinity of these genes, and in that case possible expression quantitative trait locus (eQTL) effects
Summary
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. We hypothesized that oncogenic cooperation of driver-mutations with specific regulatory germline variants may explain inter-individual diversity of clinical outcomes in cancer We explore this possibility in EwS, which constitutes a genuine model to study such cooperation for several reasons: First, it is characterized by a simple, nearly diploid genome with a single driver-mutation resulting from chromosomal rearrangements fusing the EWSR1 gene to various members of the ETS family of transcription factors (in 85% FLI1)[2,3,12,13,14]. The enhancer activity of EWSR1-FLI1-bound GGAA-microsatellites strongly depends on the inter-individually variable number of consecutive GGAA-repeats[16,17,19] Together, these characteristics provide an ideal framework to analyze how cooperation of a dominant oncogene (here EWSR1-FLI1) with polymorphic germline regulatory elements (here GGAA-microsatellites) influences the expression of disease-promoting genes that could explain clinical diversity in cancer. We show, in the EwS model, how such cooperation steers the expression of the functionally and clinically relevant EWSR1-FLI1 target gene MYBL2, thereby determining tumor growth, patient survival, and drug response
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