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.

中文翻译：

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RAD21 是尤文肉瘤中 8 号染色体增加以减轻复制压力的驱动因素

非整倍体，定义为全染色体的获得或损失，会引起细胞压力，但矛盾的是，它在癌症中经常发生。在这里，我们调查了为什么约 50% 的尤文肉瘤在EWS-FLI1融合癌基因的驱动下具有第 8 号染色体增益。所述的表达EWS-FLI1在原代细胞融合导致可导致细胞衰老复制压力。使用进化方法，我们表明三体 8通过获得RAD21的副本来减轻EWS-FLI1诱导的复制压力。RAD21的低水平异位表达足以抑制复制应激并改善EWS-FLI1 的增殖- 表达细胞。相反，删除 8 三体细胞中的一个拷贝在很大程度上抵消了 8 号染色体增益的适应性益处，并降低了软琼脂分析中尤文肉瘤癌细胞系的致瘤性。我们提出RAD21通过单基因拷贝增益促进肿瘤发生。这些基因可以解释癌症中的一些复发性非整倍性。