Chromosome 8 gain drives poor patient outcome via expression of 4E-BP1 in Ewing sarcoma

ABSTRACT Chromosome 8 (chr8) gains are common in cancer. However, their potential contribution to tumor heterogeneity is largely unexplored. Ewing sarcoma (EwS) is characterized by pathognomonic FET::ETS fusions, but show a general paucity of other recurrent somatic mutations that could explain the observed clinical diversity. In EwS, chr8 gains are the second most common genetic alteration rendering EwS an ideal model to investigate the relevance of chr8 gains in an otherwise silent genomic context. Here, we report that chr8 gain-driven gene expression patterns correlate with poor overall survival of EwS patients. This effect is predominantly mediated by increased expression of the translation initiation factor binding protein 4E-BP1 encoded by EIF4EBP1 on chr8. High EIF4EBP1 expression showed the strongest association with poor overall patient survival among all chr8-encoded genes and correlated with chr8 gains in EwS tumors. Similar findings were made in numerous entities of The Cancer Genome Atlas (TCGA). In the EwS model, silencing of 4E-BP1 reduced cell proliferation, clonogenicity, spheroidal growth in vitro , and tumorigenesis in vivo . Integrated multi- omics profiling uncovered that 4E-BP1 orchestrates a multifunctional proteomic network including hubs affecting RNA processing, translational regulation, and chromatin modification. Drug screens and functional assays revealed that high 4E-BP1 expression sensitizes for pharmacological CDK4/6 inhibition in preclinical models. Collectively, we establish chr8 gains and high 4E-BP1 expression as prognostic biomarkers in EwS and demonstrate that their association with poor patient outcome is primarily mediated by 4E-BP1 orchestrating a multifunctional proteomic network sensitizing EwS for CDK4/6 inhibitors. Our data suggest that testing for chr8 gain may improve risk-stratification and therapeutic management in EwS and other cancers.