David H. Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility, Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Genes Dev. 2021 Apr 1;35(7-8):556-572. doi: 10.1101/gad.345454.120. Epub 2021 Mar 25.
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.
非整倍体，定义为整条染色体的增益或缺失，会导致细胞应激，但矛盾的是，它在癌症中经常发生。在这里，我们研究了为什么由融合致癌基因驱动的 50%左右的尤因肉瘤会发生 8 号染色体增益。在原代细胞中表达融合蛋白会导致复制应激，从而导致细胞衰老。通过进化方法，我们表明，三体 8 号染色体通过获得一个 的拷贝来减轻 诱导的复制应激。低水平异位表达 足以减轻复制应激并改善表达细胞的增殖。相反，在三体 8 号细胞中删除一个拷贝，在很大程度上消除了 8 号染色体增益的适应性益处，并降低了尤因肉瘤癌细胞系在软琼脂测定中的致瘤性。我们提出， 通过单基因拷贝增益促进肿瘤发生。此类基因可能解释了癌症中一些反复出现的非整倍体。
