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

Joshua J. Meeks*, Hikmat Al-Ahmadie, Bishoy M. Faltas, John A. Taylor, Thomas W. Flaig, David J. DeGraff, Emil Christensen, Benjamin L. Woolbright, David J. McConkey, Lars Dyrskjøt

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

116 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)259-270
Number of pages12
JournalNature Reviews Urology
Volume17
Issue number5
DOIs
StatePublished - May 1 2020

Funding

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.

ASJC Scopus subject areas

  • Urology

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