小柯机器人

美国斯坦福大学Paul S. Mischel，Howard Y. Chang，美国加州大学圣地亚哥分校Vineet Bafna和中山大学Weini Huang共同合作近期取得重要工作进展，他们研究发现了人类癌症中染色体外DNA的进化动力学。相关论文于2022年9月19日在线发表于《自然—遗传学》杂志上。

研究人员整合了随机分离、无偏差图像分析、基于CRISPR的ecDNA标记、活细胞成像和CRISPR-C的理论模型，证明随机ecDNA遗传导致广泛的肿瘤内ecDNA拷贝数异质性和快速适应代谢应激和靶向治疗。观察到的ecDNA有益于宿主细胞的存活或生长，并且可以在单个细胞周期内发生变化。ecDNA遗传可以先验地预测含有ecDNA的癌症的一些侵袭性特征。ecDNA以一种通过染色体癌基因扩增无法实现的方式快速适应基因组的能力促进了这些特性。这些结果表明ecDNA的非染色体随机遗传模式导致癌症患者的不良预后的机理。

据了解，染色体外DNA（ecDNA）上的癌基因扩增是一种常见的事件，驱动肿瘤的侵袭性生长，耐药和缩短生存期。目前，人们对非染色体癌基因遗传的影响（随机的血统身份特征）了解的比较少，ecDNA对体细胞变异和选择的影响也同样不清楚。

附：英文原文

Title: The evolutionary dynamics of extrachromosomal DNA in human cancers

Author: Lange, Joshua T., Rose, John C., Chen, Celine Y., Pichugin, Yuriy, Xie, Liangqi, Tang, Jun, Hung, King L., Yost, Kathryn E., Shi, Quanming, Erb, Marcella L., Rajkumar, Utkrisht, Wu, Sihan, Taschner-Mandl, Sabine, Bernkopf, Marie, Swanton, Charles, Liu, Zhe, Huang, Weini, Chang, Howard Y., Bafna, Vineet, Henssen, Anton G., Werner, Benjamin, Mischel, Paul S.

Issue&Volume: 2022-09-19

Abstract: Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.

DOI: 10.1038/s41588-022-01177-x

Source: https://www.nature.com/articles/s41588-022-01177-x

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
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投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex