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Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer

Subjects

Key Points

  • Parallel efforts from three independent groups have identified basal and luminal intrinsic subtypes of muscle-invasive bladder cancer

  • Bladder cancer subtypes closely resemble corresponding subtypes of breast cancers

  • Basal bladder cancers are enriched with biomarkers associated with stem cells and epithelial-to-mesenchymal transition, and are associated with shorter disease-specific survival than luminal subtypes

  • p53-like bladder tumours are resistant to neoadjuvant chemotherapy

  • Each bladder cancer subtype contains clinically actionable biological targets, including EGFR, STAT3, HIF-1, FGFR3, ERBB2, ERBB3, and PPARG

Abstract

Whole-genome analyses have revealed that muscle-invasive bladder cancers (MIBCs) are heterogeneous and can be grouped into basal and luminal subtypes that are highly reminiscent of those found in breast cancer. Basal MIBCs are enriched with squamous and sarcomatoid features and are associated with advanced stage and metastatic disease at presentation. Like basal breast cancers, basal bladder tumours contain a claudin-low subtype that is enriched with biomarkers characteristic of epithelial-to-mesenchymal transition. The stem cell transcription factor ΔNp63α controls basal MIBC gene expression, just as it does in basal breast cancers. Luminal MIBCs are enriched with activating FGFR3 and ERBB3 mutations and ERBB2 amplifications, and their gene expression profiles are controlled by peroxisome proliferator activator receptor γ (PPARγ) and possibly also by oestrogen receptor activation. Luminal bladder cancers can be further subdivided into two subtypes, p53-like and luminal, which can be distinguished from one another by different levels of biomarkers that are characteristic of stromal infiltration, cell cycle progression, and proliferation. Importantly, basal bladder cancers are intrinsically aggressive, but are highly sensitive to cisplatin-based combination chemotherapy. Although the luminal subtypes are not as intrinsically aggressive as basal cancers, p53-like tumours are resistant to chemotherapy and might, therefore, represent a problem for treated patients.

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Figure 1: Major biomarkers in the intrinsic basal and luminal subtypes.
Figure 2: Possible origins and transcriptional control of basal and luminal MIBCs.
Figure 3: Correspondence between the intrinsic subtypes of bladder and breast cancers.
Figure 4: Relationships between the bladder cancer subtypes identified by the groups at MDA, UNC, TCGA, and Lund.

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C.D. and D.J.M. researched, wrote, edited, and discussed the article with colleagues. W.C., A.O., X.S. and A.S.-R. contributed towards researching and reviewing the paper, as well as discussions of contents. B.C. researched and reviewed the manuscript prior to submission.

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Correspondence to David J. McConkey.

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Choi, W., Czerniak, B., Ochoa, A. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 11, 400–410 (2014). https://doi.org/10.1038/nrurol.2014.129

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