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

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 fusion oncogene, harbor chromosome 8 gains. Expression of the fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates -induced replication stress through gain of a copy of Low-level ectopic expression of is sufficient to dampen replication stress and improve proliferation in -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 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.