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Using genome-graph analyses, the work links frequent ecDNA-forming amplifications to mutation timing, showing CCND1 amplifications arise within ecDNA and persist to expand complexity and treatment resistance. Long-read sequencing and modeling validate ecDNA as a treatment-resistance 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[https://doi.org/10.1038/s41586-024-07955-3](https://doi.org/10.1038/s41586-024-07955-3)\u003Cbr>Received: 28 April 2023 Accepted: 14 August 2024 Published online: 9 October 2024 Open access\u003Cbr> Check for updates | Duy D. Nguyen1,12, William F. Hooper2,12, Weisi Liu1,12, Timothy R. Chu2, Heather Geiger2, Jennifer M. Shelton2, Minita Shah2, Zoe R. Goldstein2, Lara Winterkorn2, Adrienne Helland2, Michael Sigouros3, Jyothi Manohar3, Jenna Moyer3, MajdAl Assaad3, Alissa Semaan3, Sandra Cohen3,4, Florencia Madorsky Rowdo3,5, David Wilkes3, Mohamed Osman1,\u003Cbr>Rahul R. Singh1, Andrea Sboner3,4,5, Henkel L. Valentine6, Phillip Abbosh6,7,\u003Cbr>Scott T. Tagawa1,3,8,9, David M. Nanus1,3,8,9, Jones T. Nauseef1,3,8, Cora N. Sternberg1,3,8, Ana M. Molina1,3,8, Douglas Scherr8,9, Giorgio Inghirami3,4,8, Juan Miguel Mosquera3,4,8, Olivier Elemento3,4,5,8,10,13, Nicolas Robine2,13 & Bishoy M. Faltas1,3,8,10,11,13✉\u003Cbr>Advanced urothelialcancerisa 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 signaturesand 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 clonaland 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 patternsofAPOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative toecDNAbiogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNAforming 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 ofCCND1 ecDNA confirmed its role asa driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications. |  |\n| Mutagenesis and DNA repair constantly interact during cancer, result- |  | ecDNA, shape UC evolution and drug resistance. Our ability to predict |\n| ing indistinct mutational signaturesand extensive structural genomic |  | the clinical trajectory and prevent drug resistance in patients with |\n| changes. Theapolipoprotein B mRNA-editing enzyme catalytic subu- |  | advanced cancer depend on answering these fundamental questions. |\n| nit 3 (APOBEC3) cytidine deaminases3 cause somatic mutational sig- |  | To address these questions, we performed whole-genome sequenc- |\n| natures characterized by cytosine to thymine or guanine substitutions |  | ing (WGS) of matched sets of primary and metastatic UC tumours |\n| in the genomes of various human cancers, especially urothelial carci- |  | and morphologically normal urothelial samples. We analysed single |\n| noma (UC)3–5. In a previous study1, we investigated the evolutionary |  | base substitution (SBS), doublet base substitution (DBS) and small |\n| dynamics of chemotherapy-resistant advancedUC. However, several |  | insertion and deletion (indel; ID) mutational signaturesand superim- |\n| fundamental questions remain: (1) how and whether the relative timing, |  | posed them on phylogenetic maps of primary and metastatic tumours |\n| clonality and velocity of endogenous mutagenic stresses (for example, APOBEC3) ","cbCaipmMdZLXUukz","https://ap.wps.com/l/cbCaipmMdZLXUukz","pdf",37083375,36,"English","# Abstract\n# Study design and rationale\n## Mutational signatures and phylogenetic analyses\n## Structural variants and ecDNA genome graphs\n# Key findings\n## APOBEC3 versus chemotherapy mutation timing\n## ecDNA-forming SVs and CCND1 amplification\n# Validation and implications\n## Long-read sequencing and de novo assembly","[{\"question\":\"How do APOBEC3-induced mutations and chemotherapy-induced mutations differ over tumor evolution?\",\"answer\":\"APOBEC3-induced mutations are clonal and occur early, whereas chemotherapy induces mutational bursts consisting of hundreds of late subclonal mutations.\"},{\"question\":\"What role do extrachromosomal DNA (ecDNA)-forming structural variants play in urothelial cancer?\",\"answer\":\"ecDNA-forming SVs show frequent high copy-number circular amplicons, persist and increase in complexity, and contribute to the evolution of treatment resistance.\"},{\"question\":\"How did the study identify and validate CCND1 ecDNA as a driver of treatment resistance?\",\"answer\":\"The researchers used long-read whole-genome sequencing and de novo assembly to map CCND1 ecDNA structure, then used experimental modeling of CCND1 ecDNA to confirm its driver role in treatment resistance.\"}]","The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution - Research paper | PDF",1790023659,91]