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Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the  EWS-FLI1  fusion oncogene, harbor chromosome 8 gains. Expression of the  EWS-FLI1  fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates  EWS-FLI1 -induced replication stress through gain of a copy of  RAD21.  Low-level ectopic expression of  RAD21  is sufficient to dampen replication stress and improve proliferation in  EWS-FLI1 -expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that  RAD21  promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.

RAD21 is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress