Cited by 210Cancer Genomics and DiagnosticsBladder and Urothelial Cancer TreatmentsNephrotoxicity and Medicinal Plants

Macroscopic somatic clonal expansion in morphologically normal human urothelium

Li, Ruoyan, Du, Yiqing, Chen, Zhanghua, Xu, Deshu, Lin, Tianxin, Jin, Shanzhao, Wang, Gongwei, Liu, Ziyang +4 more·2020·Science

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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Crossref · 10.1126/science.aba7300

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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
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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