美国耶鲁大学Roel G. W. Verhaak等研究人员合作在癌症进展过程中绘制细胞外染色体DNA的扩增图谱。相关论文于2024年10月14日在线发表在《自然—遗传学》杂志上。

为了理解染色体外DNA（ecDNA）扩增在癌症进展中的作用，研究人员检测并分类了8060例新诊断的原发性癌症、未经治疗的转移性癌症和经过多次治疗的肿瘤中的局部扩增现象。结果显示，未经治疗的转移性肿瘤和经过多次治疗的肿瘤中ecDNA的检测频率显著高于新诊断的癌症。尤其是化疗后处理的患者，其肿瘤中的ecDNA频率明显高于未经治疗的癌症。

此外，微管蛋白抑制与ecDNA的增加相关，提示ecDNA在治疗反应中可能发挥作用。在纵向匹配的肿瘤样本中，ecDNA相较于染色体扩增更可能被保留。时间点间共享的ecDNA，以及晚期癌症中的ecDNA，比新诊断肿瘤中的私有ecDNA更容易发生局部高突变事件。ecDNA局部高突变的较高变异等位基因比例暗示了ecDNA早期突变过程。这些研究结果表明，ecDNA可能为肿瘤在癌症进展和转移过程中提供竞争优势。

附：英文原文

Title: Mapping extrachromosomal DNA amplifications during cancer progression

Author: Kim, Hoon, Kim, Soyeon, Wade, Taylor, Yeo, Eunchae, Lipsa, Anuja, Golebiewska, Anna, Johnson, Kevin C., An, Sepil, Ko, Junyong, Nam, Yoonjoo, Lee, Hwa Yeon, Kang, Seunghyun, Chung, Heesuk, Niclou, Simone P., Moon, Hyo-Eun, Paek, Sun Ha, Bafna, Vineet, Luebeck, Jens, Verhaak, Roel G. W.

Issue&Volume: 2024-10-14

Abstract: 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.

DOI: 10.1038/s41588-024-01949-7

Source: https://www.nature.com/articles/s41588-024-01949-7