To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis.

为了了解染色体外 DNA （ecDNA） 扩增在癌症进展中的作用，我们在 8,060 例新诊断的原发性癌症、未经治疗的转移瘤和经过大量预处理的肿瘤中检测和分类了局灶性扩增。与新诊断的癌症相比，在未经治疗的转移性和既往肿瘤中检测到 ecDNA 的频率显着更高。与未治疗的癌症相比，化疗前患者肿瘤的 ecDNA 频率显著更高。特别是，与 ecDNA 相关的微管蛋白抑制增加，表明 ecDNA 在治疗反应中的作用。在纵向匹配的肿瘤样本中，与染色体扩增相比，ecDNA 更有可能被保留。在时间点之间共享的 ecDNA，与新诊断肿瘤中的私有 ecDNA 和 ecDNA 相比，晚期癌症中的 ecDNA 更有可能携带局部超突变事件。ecDNA 定位超突变的相对较高的变异等位基因分数与早期 ecDNA 诱变有关。我们的研究结果提名 ecDNA 在癌症进展和转移过程中为肿瘤提供竞争优势。