Extrachromosomal DNA in urothelial carcinoma: mechanisms and clinical applications

Extrachromosomal DNA (ecDNA) has emerged as a major driver of genomic instability and rapid tumour evolution in urothelial carcinoma. In urothelial carcinoma, ecDNA amplifies oncogenes, reshapes 3D chromatin interactions, reprogrammes transcription and modulates the tumour-immune interface. Together, these features fuel intratumour heterogeneity, accelerate APOBEC3-associated mutational evolution and contribute to aggressive disease. Advances in sequencing and imaging technologies have greatly expanded our understanding of ecDNA biology. Importantly, ecDNA can be detected through non-invasive liquid biopsies, including urine and plasma, and inferred from standard histopathology slides via digital pathology. These observations suggest that ecDNA could be a valuable adjunct biomarker, enhancing current strategies for early detection, patient stratification and dynamic monitoring of treatment response.