Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon-si, South Korea.
Department of Biohealth Regulatory Science, School of Pharmacy, Sungkyunkwan University, Suwon-si, South Korea.
Nat Genet. 2024 Nov;56(11):2447-2454. doi: 10.1038/s41588-024-01949-7. Epub 2024 Oct 14.
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.
为了理解额外染色体 DNA（ecDNA）扩增在癌症进展中的作用，我们在 8060 例新诊断的原发性癌症、未经治疗的转移灶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，未经治疗的转移性和预处理肿瘤中 ecDNA 的检出频率明显更高。与未经治疗的癌症相比，来自化疗预处理患者的肿瘤显示出更高的 ecDNA 频率。特别是，与 ecDNA 增加相关的微管蛋白抑制表明 ecDNA 在治疗反应中起作用。在纵向匹配的肿瘤样本中，ecDNA 比染色体扩增更有可能保留。在时间点之间共享的 ecDNA 以及晚期癌症中的 ecDNA 比私有 ecDNA 和新诊断肿瘤中的 ecDNA 更有可能携带局部超突变事件。ecDNA 局部突变的相对高变异等位基因分数暗示了早期 ecDNA 突变。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。
