美国威尔康奈尔医学院Bishoy M. Faltas团队近期取得重要工作进展，他们研究提出突变和ecDNA的相互作用影响尿路上皮癌的演变。相关研究成果2024年10月9日在线发表于《自然》杂志上。

据介绍，晚期尿路上皮癌是一种常见的致死性疾病，其特征是明显的遗传异质性。

研究人员探讨了由内源性和外源性诱变过程引起的基因组特征的演化及其与复杂结构变异（SV）的相互作用。研究人员叠加了癌症患者匹配序列肿瘤的突变特征和系统发育分析，以确定这些过程的演化动力学。研究人员发现APOBEC3诱导的突变是克隆性和早期的，而化疗诱导了数百个晚期亚克隆突变的突变爆发。

使用基因组图计算工具，研究人员观察到形成SV的染色体外DNA（ecDNA）的常见高拷贝数环状扩增子，并描述了形成SV的ecDNA内APOBEC3诱导和化疗诱导突变的不同时间模式，从而对这些突变过程相对于ecDNA生物合成的时间获得了新的见解。癌症尿路上皮中大多数CCND1扩增发生在环状形成ecDNA的SV中。

形成ecDNA的SV持续存在，复杂性增加，包含额外的DNA片段，并有助于治疗耐药性的演化。牛津纳米孔技术长读全基因组测序，然后重头组装，绘制出CCND1 ecDNA结构。CCND1 ecDNA的实验建模证实了其作为治疗耐药性驱动因素的作用。

总之，这一研究结果确定了驱动癌症尿路上皮演变的基本机制，并具有重要的治疗意义。

附：英文原文

Title: The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution

Author: Nguyen, Duy D., Hooper, William F., Liu, Weisi, Chu, Timothy R., Geiger, Heather, Shelton, Jennifer M., Shah, Minita, Goldstein, Zoe R., Winterkorn, Lara, Helland, Adrienne, Sigouros, Michael, Manohar, Jyothi, Moyer, Jenna, Al Assaad, Majd, Semaan, Alissa, Cohen, Sandra, Madorsky Rowdo, Florencia, Wilkes, David, Osman, Mohamed, Singh, Rahul R., Sboner, Andrea, Valentine, Henkel L., Abbosh, Phillip, Tagawa, Scott T., Nanus, David M., Nauseef, Jones T., Sternberg, Cora N., Molina, Ana M., Scherr, Douglas, Inghirami, Giorgio, Mosquera, Juan Miguel, Elemento, Olivier, Robine, Nicolas, Faltas, Bishoy M.

Issue&Volume: 2024-10-09

Abstract: Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

DOI: 10.1038/s41586-024-07955-3

Source: https://www.nature.com/articles/s41586-024-07955-3