The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution

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

Nature, 2024, vol. 635, issue 8037, 219-228

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07955-3

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