The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution

• 成果类型: Article
• 署名作者: 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; Rowdo, Florencia Madorsky; 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.
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Fox Chase Cancer Center; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4574
• DOI: 10.1038/s41586-024-07955-3
• 发表日期: 2024-11-07
• 页码: 219-+
• 关键词: structural variation; molecular classification; mutational signatures; extrachromosomal dna; clonal evolution; genome; tumor; database; selection; variants

摘要

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity(1). 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 tool(2), 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.