Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.

全染色体和臂水平拷贝数改变在肿瘤中发生频率很高，但它们的选择性优势（如果有的话）却知之甚少。在这里，利用无偏见的全染色体遗传筛选与体外进化相结合来产生臂和亚臂水平的事件，我们从非整倍体化的人肾和乳腺上皮细胞中迭代地选择最合适的核型。这些上皮细胞系中基于增殖的核型选择模拟了在没有驱动突变的情况下患者群体中组织特异性肿瘤非整倍性模式。基于 Hi-C 的易位图谱显示，臂水平事件通常通过着丝粒易位以两倍的倍数出现，并且在四倍体中比二倍体更频繁地发生，从而导致四倍体种群进化中多样性的增加。同基因克隆谱系能够阐明与常见拷贝数改变相关的促肿瘤发生机制，揭示Notch信号传导增强是乳腺癌1q增益的驱动因素。我们认为内在的、组织特异性的增殖效应是癌症中肿瘤拷贝数模式的基础。