The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

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.

SUBMITTER: Nguyen DD 

PROVIDER: S-EPMC11541202 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature