Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Experimental and Clinical Research Center of the MDC and Charité Berlin, Berlin, Germany.
Nat Genet. 2022 Feb;54(2):107-114. doi: 10.1038/s41588-021-01000-z. Epub 2022 Feb 10.
Extrachromosomal DNA (ecDNA) amplification has been observed in at least 30 different cancer types and is associated with worse patient outcomes. This has been linked to increased oncogene dosage because both oncogenes and associated enhancers can occupy ecDNA. New data challenge the view that only oncogene dosage is affected by ecDNA, and raises the possibility that ecDNA could disrupt genome-wide gene expression. Recent investigations suggest that ecDNA localizes to specialized nuclear bodies (hubs) in which they can act in trans as ectopic enhancers for genes on other ecDNA or chromosomes. Moreover, ecDNA can reintegrate into the genome, possibly further disrupting the gene regulatory landscape in tumor cells. In this Perspective, we discuss the emerging properties of ecDNA and highlight promising avenues to exploit this new knowledge for the development of ecDNA-directed therapies for cancer.
染色体外 DNA（ecDNA）扩增至少在 30 种不同的癌症类型中被观察到，并与患者预后较差相关。这与致癌基因剂量增加有关，因为致癌基因和相关增强子都可以占据 ecDNA。新的数据挑战了仅致癌基因剂量受 ecDNA 影响的观点，并提出了 ecDNA 可能破坏全基因组基因表达的可能性。最近的研究表明，ecDNA 定位于专门的核体内（中心），在这些核体内，它们可以作为异位增强子，对其他 ecDNA 或染色体上的基因进行反式作用。此外，ecDNA 可以重新整合到基因组中，可能进一步破坏肿瘤细胞中的基因调控景观。在这篇观点文章中，我们讨论了 ecDNA 的新兴特性，并强调了利用这一新知识开发针对 ecDNA 的癌症治疗方法的有前途的途径。
