Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

染色体外 DNA (ecDNA) 上的癌基因扩增是一种常见事件，会导致肿瘤的侵袭性生长、耐药性和较短的生存期。目前，人们对非染色体癌基因遗传（血统随机身份）的影响知之甚少。 ecDNA 对体细胞变异和选择的影响也不清楚。在这里，我们将随机分离、无偏图像分析、基于 CRISPR 的 ecDNA 标记与活细胞成像和 CRISPR-C 的理论模型相结合，证明随机 ecDNA 遗传导致广泛的肿瘤内 ecDNA 拷贝数异质性以及对代谢应激和靶向治疗的快速适应。观察到的 ecDNA 有利于宿主细胞的存活或生长，并且可以在单个细胞周期内发生变化。 ecDNA 遗传可以先验地预测含有 ecDNA 的癌症的一些侵袭性特征。 ecDNA 能够以染色体癌基因扩增无法实现的方式快速适应基因组，从而促进了这些特性。这些结果表明 ecDNA 的非染色体随机遗传模式如何导致癌症患者的不良预后。