英国伦敦大学Charles Swanton团队研究了染色体外DNA的起源和影响。相关论文于2024年11月6日发表在《自然》杂志上。
据了解，染色体外DNA （ecDNA）是癌症患者治疗耐药和预后不良的主要因素。
研究小组研究了癌症中ecDNA元件的多样性，揭示了相关的组织、遗传和突变背景。通过分析来自10万基因组计划的39种肿瘤类型的14778名患者的数据，研究人员证明17.1%的肿瘤样本含有ecDNA。
研究人员揭示了一种模式，高度显示基于组织背景的ecDNAs选择，将其基因组内容与其起源组织联系起来。研究人员表明，ecDNA不仅是驱动癌基因扩增的机制，而且也是经常扩增免疫调节和炎症基因的机制，例如那些调节淋巴细胞介导的免疫和免疫效应过程的基因。
此外，携带免疫调节基因的ecDNAs与肿瘤T细胞浸润减少有关。该团队鉴定出仅携带增强子、启动子和lncRNA元件的ecDNAs，这表明在反式中ecDNAs之间的相互作用具有组合能力。
研究人员还确定了与ecDNA相关的内在和环境突变过程，包括与其形成（如烟草暴露）和进展（如同源重组修复缺陷）相关的过程。临床上，ecDNA检测与肿瘤分期相关，在靶向治疗和细胞毒性治疗后更为普遍，与转移和较短的总生存期相关。这些结果揭示了为什么ecDNA是一个重要的临床问题，它可以协同驱动肿瘤生长信号，改变转录图谱和抑制免疫系统。
附：英文原文
Title: Origins and impact of extrachromosomal DNA
Author: Bailey, Chris, Pich, Oriol, Thol, Kerstin, Watkins, Thomas B. K., Luebeck, Jens, Rowan, Andrew, Stavrou, Georgia, Weiser, Natasha E., Dameracharla, Bhargavi, Bentham, Robert, Lu, Wei-Ting, Kittel, Jeanette, Yang, S. Y. Cindy, Howitt, Brooke E., Sharma, Natasha, Litovchenko, Maria, Salgado, Roberto, Hung, King L., Cornish, Alex J., Moore, David A., Houlston, Richard S., Bafna, Vineet, Chang, Howard Y., Nik-Zainal, Serena, Kanu, Nnennaya, McGranahan, Nicholas, Flanagan, Adrienne M., Mischel, Paul S., Jamal-Hanjani, Mariam, Swanton, Charles
Issue&Volume: 2024-11-06
Abstract: Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.
DOI: 10.1038/s41586-024-08107-3
Source: https://www.nature.com/articles/s41586-024-08107-3
来源：科学网 小柯机器人