Macroscopic somatic clonal expansion in morphologically normal human urothelium
Abstract
Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53 , PIK3CA , and FGFR3 KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.
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Somatic variants accumulate in all cell types that have been studied, both during normal development and during aging.
“Somatic variants accumulate in all cell types that have been studied, both during normal development and during aging16–18.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [17]
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- Authors
- Li, R., Du, Y., Chen, Z., Xu, D., Lin, T., Jin, S., Wang, G., Liu, Z., Lu, M., Chen, X., Xu, T., & Bai, F.
- Affiliations
- Peking University (CN)
- Peking University People's Hospital (CN)
- Sun Yat-sen University (CN)
- Corresponding author
- Li, Ruoyan
- Du, Yiqing
- Chen, Zhanghua
- Xu, Deshu
- Lin, Tianxin
- Xu, Tao
- Bai, Fan
- ORCID
- Venue
- Science
- Published
- 2020-10-02
- Volume
- 370
- Issue
- 6512
- Pages
- 82-89
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3091186260
- Cited by
- 206
- References
- 68
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 43 · 2023: 25 · 2022: 48 · 2021: 36 · 2020: 7
- FWCI
- 10.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Nephrotoxicity and Medicinal Plants
- Keywords
- urothelium, urinary bladder, mutational landscape, mutational heterogeneity, aristolochic acid, tobacco carcinogens, mutational processes, bladder cancer, laser microdissection
- MeSH terms
- Urinary Bladder Neoplasms, DNA-Binding Proteins, Humans, Mutagens, Mutation, Neoplasm Proteins, Tumor Suppressor Protein p53, Mutagenesis, Urothelium, Aristolochic Acids, Chromatin Assembly and Disassembly, Receptor, Fibroblast Growth Factor, Type 3, Histone Demethylases, Class I Phosphatidylinositol 3-Kinases
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