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Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes

Nature Reviews Urology volume 17, pages 259–270 (2020)Cite this article

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Abstract

Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.

Key points

  • Bladder cancers have a high total mutational burden and considerable intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels that remain difficult to quantify.

  • Heterogeneity might be driven by genomic events initiated by APOBEC enzymes and selection pressure from therapeutic interventions, which both drive tumour evolution.

  • Bladder tumours can be categorized into different subtypes on the basis of gene expression signatures, but these molecular subtypes might be unstable and different subtypes can occur within the same tumour causing intratumoural heterogeneity.

  • Variant tumour histologies are the morphological extreme of tumour heterogeneity and include glandular, squamous, nested, plasmacytoid, micropapillary, sarcomatoid and small-cell carcinoma.

  • Tumour heterogeneity might affect treatment efficacy, for example, of neoadjuvant chemotherapy and immune checkpoint inhibitors, as well as targeted therapy, for example, when individual actionable mutations only occur in a fraction of the tumour.

  • Biomarkers to select personalized treatments in precision medicine approaches will likely shape future clinical trial design, but their validity might be affected by heterogeneity.

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Fig. 1: Different types of heterogeneity found in bladder cancer.
Fig. 2: Tumour evolution with emergence of distinct tumour subtypes.
Fig. 3: Variant histology of urothelial carcinoma.

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Acknowledgements

The authors acknowledge the Leo and Anne Albert Institute of Bladder Cancer Research. J.J.M. is supported by a VA Merit Award (BX003692-01) and a Department of Defense Grant (W81XWH-18-0257). J.J.M and L.D. are supported by an award from the Leo and Anne Albert Institute of Bladder Cancer Research. H.A. is supported by a Sloan Kettering Institute for Cancer Research Cancer Center Support Grant P30CA008748 and SPORE in Bladder Cancer P50CA221745. B.M.F. is supported by the Department of Defense CDMRP Career Development Award (grant CA160212). D.J.D. is supported in part by RSG 17-233-01-TBE from the American Cancer Society. B.L.W. is supported by an American Urological Association Research Scholar Award.

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Authors and Affiliations

  1. Departments of Urology and Biochemistry, Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Joshua J. Meeks

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Hikmat Al-Ahmadie

  3. Department of Medicine and Department of Cell and Developmental biology, Weill-Cornell Medicine, New York, NY, USA

    Bishoy M. Faltas

  4. Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

    John A. Taylor III & Benjamin L. Woolbright

  5. University of Colorado Cancer Center, Aurora, CO, USA

    Thomas W. Flaig

  6. Departments of Pathology, Biochemistry & Molecular Biology and Surgery, Division of Urology, Pennsylvania State University, College of Medicine, Hershey, PA, USA

    David J. DeGraff

  7. Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark

    Emil Christensen & Lars Dyrskjøt

  8. Johns Hopkins Greenberg Bladder Cancer Institute, Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA

    David J. McConkey

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Contributions

J.J.M., H.A., B.M.F., J.A.T.III, T.W.F., E.C., B.L.W., D.J.M., L.D. researched data for the article and wrote the manuscript. All authors made substantial contributions to discussion of the article content and reviewed and/or edited the manuscript before submission.

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Correspondence to Joshua J. Meeks.

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Competing interests

B.M.F. received grant/research support from Eli Lilly and Company and participated in an Advisory Board for Immunomedics. J.J.M. received research support from Epizyme, Tesaro and Abbvie, is a consultant for Ferring and AstraZeneca, and participated in advisory boards for Cold Genesys and Janssen. H.A. is a consultant for AstraZeneca/MedImmune, Bristol-Myers Squibb and EMD Serono. L.D. received research support from Ferring and Natera, and is a consultant for Ferring.

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Nature Reviews Urology thanks P. Black, R. Bryan and A. Hartmann for their contribution to the peer review of this work.

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Meeks, J.J., Al-Ahmadie, H., Faltas, B.M. et al. Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes. Nat Rev Urol 17, 259–270 (2020). https://doi.org/10.1038/s41585-020-0304-1

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