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Extrachromosomal DNA in urothelial carcinoma: mechanisms and clinical applications

Nature Reviews Urology (2026)Cite this article

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Abstract

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.

Key points

  • Extrachromosomal DNA (ecDNA) occurs in more than one-third of urothelial carcinomas and some precancerous lesions, driving strong oncogene amplification and defining a TP53 and chromothripsis-associated evolutionary trajectory distinct from the indolent FGFR3-mutant pathway.

  • ecDNA shapes clonal evolution in urothelial carcinoma by enabling rapid copy-number remodelling and interacting with mutational processes such as APOBEC3-driven mutagenesis, thereby promoting tumour adaptation and multifocality.

  • ecDNA confers selective advantages under therapeutic stress and promotes immune evasion, in part by downregulating major histocompatibility complex class I expression in urothelial carcinoma cells.

  • ecDNA is detectable through urothelial carcinoma-specific liquid biopsy approaches — including urine-based and plasma-based assays — and can be inferred from routine haematoxylin-and-eosin-stained slides using emerging digital pathology tools.

  • Targeting ecDNA biology offers a potential approach to modulating oncogene amplification and therapeutic resistance, and could be a promising avenue for future therapeutic development.

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Fig. 1: Hallmarks of extrachromosomal DNA.
Fig. 2: Dynamic life cycle of extrachromosomal DNA in cancer genomes.
Fig. 3: Extrachromosomal DNA shapes urothelial carcinoma evolution.
Fig. 4: Translational opportunities of extrachromosomal DNA in urothelial carcinoma.

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Acknowledgements

The authors thank all members of the W.L. Lab for their constructive suggestions.

Author information

Author notes

  1. These authors contributed equally: Conghui Li, Zhiqiang Hu, Weimin Zhang, Yongling Ji, Fubing Wang.

  2. These authors jointly supervised this work: Conghui Li, Fengbiao Mao, Chunhua Lin, Wei Lv.

Authors and Affiliations

  1. Department of Biology, University of Copenhagen, Copenhagen, Denmark

    Conghui Li  (李聪慧)

  2. Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China

    Zhiqiang Hu  (胡志强)

  3. State Key Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China

    Weimin Zhang  (张维敏)

  4. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China

    Yongling Ji  (季永领), Yuchen Zeng  (曾雨晨) & Wei Lv  (吕伟)

  5. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China

    Fubing Wang  (汪付兵)

  6. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Sanju Sinha

  7. Cancer Center, Peking University Third Hospital, Beijing, China

    Fengbiao Mao  (毛凤彪)

  8. Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China

    Fengbiao Mao  (毛凤彪)

  9. The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China

    Chunhua Lin  (林春华)

  10. Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Wei Lv  (吕伟)

Authors
  1. Conghui Li  (李聪慧)
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  2. Zhiqiang Hu  (胡志强)
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  3. Weimin Zhang  (张维敏)
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  4. Yongling Ji  (季永领)
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  5. Fubing Wang  (汪付兵)
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  6. Yuchen Zeng  (曾雨晨)
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  7. Sanju Sinha
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  8. Fengbiao Mao  (毛凤彪)
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  9. Chunhua Lin  (林春华)
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  10. Wei Lv  (吕伟)
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Contributions

C. Li, Z.H., W.Z., Y.J., C. Lin and W.L. researched data for the article. C. Li, Z.H., W.Z., F.M., Y.J. and W.L. wrote the article. All authors made substantial contributions to discussions of the content and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Conghui Li  (李聪慧), Fengbiao Mao  (毛凤彪), Chunhua Lin  (林春华) or Wei Lv  (吕伟).

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Nature Reviews Urology thanks Gabriel Malouf, Wenxuan Cheng, Yujiro Hayashi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Li, C., Hu, Z., Zhang, W. et al. Extrachromosomal DNA in urothelial carcinoma: mechanisms and clinical applications. Nat Rev Urol (2026). https://doi.org/10.1038/s41585-026-01134-x

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