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Molecular profile of bladder cancer progression to clinically aggressive subtypes

Nature Reviews Urology (2024)Cite this article

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Abstract

Bladder cancer is a histologically and clinically heterogenous disease. Most bladder cancers are urothelial carcinomas, which frequently develop distinct histological subtypes. Several urothelial carcinoma histological subtypes, such as micropapillary, plasmacytoid, small-cell carcinoma and sarcomatoid, show highly aggressive behaviour and pose unique challenges in diagnosis and treatment. Comprehensive genomic characterizations of the urothelial carcinoma subtypes have revealed that they probably arise from a precursor subset of conventional urothelial carcinomas that belong to different molecular subtypes — micropapillary and plasmacytoid subtypes develop along the luminal pathway, whereas small-cell and sarcomatoid subtypes evolve along the basal pathway. The subtypes exhibit distinct genomic alterations, but in most cases their biological properties seem to be primarily determined by specific gene expression profiles, including epithelial–mesenchymal transition, urothelial-to-neural lineage plasticity, and immune infiltration with distinct upregulation of immune regulatory genes. These breakthrough studies have transformed our view of bladder cancer histological subtype biology, generated new hypotheses for therapy and chemoresistance, and facilitated the discovery of new therapeutic targets.

Key points

  • Bladder cancer histological subtypes might progress from a common precursor — conventional urothelial carcinoma — and distinct transcriptional circuits control their biological properties.

  • The micropapillary subtype seems to evolve from the luminal pathway and is characterized by ERBB2 genomic alterations and activation of miR-296-targeted and RUVBL1-targeted genes.

  • Plasmacytoid cancer also seems to evolve from luminal urothelial carcinoma and is characterized by truncating somatic mutations in E-cadherin (CDH1).

  • The small-cell carcinoma subtype develops via the basal pathway and is characterized by urothelial-to-neural lineage plasticity and can be subdivided into molecular subtypes that resemble those found in lung cancers.

  • The sarcomatoid subtype also seems to evolve from basal urothelial carcinoma with downregulation of homotypic adherence genes and activation of epithelial–mesenchymal transition.

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Fig. 1: Bladder cancer evolution from mucosal field effects through luminal papillary and basal non-papillary pathways.
Fig. 2: Molecular classification of bladder cancer into luminal and basal subtypes.
Fig. 3: Expression pattern of basal and luminal markers in conventional urothelial carcinoma and sarcomatoid, small-cell, micropapillary and plasmacytoid bladder cancer subtypes.
Fig. 4: Dysregulation of the epithelial–mesenchymal transition network in conventional urothelial carcinoma and sarcomatoid, small-cell, micropapillary, and plasmacytoid bladder cancer subtypes.
Fig. 5: Expression pattern of immune cell infiltrate in conventional urothelial carcinoma and sarcomatoid, small-cell, micropapillary and plasmacytoid bladder cancer subtypes.

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Authors and Affiliations

  1. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Charles C. Guo, Sangkyou Lee, June G. Lee, Michael Zaleski & Bogdan Czerniak

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Huiqin Chen & Peng Wei

  3. Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA

    Woonyoung Choi & David J. McConkey

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Contributions

C.C.G., S.L., J.G.L., H.C., M.Z., W.C., P.W. and B.C. researched data for the article. C.C.G. and B.C. contributed substantially to discussion of the content. C.C.G. and B.C. wrote the article. C.C.G., D.J.M. and B.C. reviewed and/or edited the manuscript before submission.

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Correspondence to Bogdan Czerniak.

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Nature Reviews Urology thanks Liang Cheng and Veronika Weyerer for their contribution to the peer review of this work.

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Guo, C.C., Lee, S., Lee, J.G. et al. Molecular profile of bladder cancer progression to clinically aggressive subtypes. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-023-00847-7

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