Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Nature Reviews Cancer | Review
Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

Margaret A. Knowles Carolyn D. Hurst

Nature Reviews Cancer
15,
25–41
(2015)
doi:10.1038/nrc3817

Published online
23 December 2014

Abstract

Urothelial carcinoma of the bladder comprises two long-recognized disease entities with distinct molecular features and clinical outcome. Low-grade non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle-invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that traverse conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalized therapy.


At a glance


Bladder cancer is the fifth most common cancer in men in Western countries (male:female ratio is 3:1), and tobacco smoking is a major risk factor.
There are two major groups of patients with distinct prognosis and molecular features. Although local disease recurrence is a major problem for those with low-grade non-muscle-invasive tumours, life expectancy is long and development of invasive disease is infrequent. For those who present with muscle-invasive disease, development of metastatic disease is common, prognosis is dismal and no advances in therapy have been made for decades.
Major unmet clinical needs include non-invasive methods for disease surveillance and novel approaches to eliminate both tumour and widespread intraepithelial preneoplasia in patients with non-muscle-invasive disease. New systemic therapeutic approaches are urgently needed for those with muscle-invasive disease.
Recent studies reveal important biological features of urothelial metastasis and the epithelial–mesenchymal transition that may contribute to metastatic initiation. A key role for inflammatory processes is evident in the development of metastasis.
Heterogeneity in outcome within the two major groups indicates a need for subclassification for more accurate prognostication, prediction of response to current therapies and development of novel therapies.
Recent molecular analyses now provide such subclassification with definition of multiple subgroups that are independent of conventional histopathological definitions. This presents major opportunities for personalized patient care.