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.
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.
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The authors thank Cancer Research UK (C6228/A5433; C6228/A12512; C37059/A11941) and Yorkshire Cancer Research (L346, L362, L367, L372, L376PA) for past and current funding of their work. They also thank M. Höglund and K. S. Chan for discussions during the writing of this Review.
The authors declare no competing financial interests.
- Tumour–Node–Metastasis system
(TNM system). A classification system used to describe the stage of a tumour. T describes the extent of local invasion; N describes whether the tumour has spread to local lymph nodes; and M describes distant metastatic spread.
Chromosomal shattering. A phenomenon whereby cancer cells acquire many clustered chromosomal rearrangements as a single catastrophic event during tumour development.
- Non-homologous end-joining
An error-prone mechanism of DNA repair in which broken DNA ends are joined without the guidance of a large homologous template. Short homologous DNA sequences termed microhomologies are used to guide repair.
- Replication-licensing complex
A complex of proteins that assemble at origins of DNA replication during late G1 phase of the cell cycle to ensure precise and timely DNA replication.
- Homologous recombination
A high-fidelity mechanism of DNA repair that uses recombination with an intact homologous template to repair double-strand breaks.
- Bacillus Calmette–Guerin
(BCG). A vaccine used to induce immunity to tuberculosis. It is also used to treat high-risk localized bladder cancer and carcinoma in situ. Instillation of BCG into the bladder induces a localized immune response that is able to eliminate cancer cells. For bladder cancer treatment, a course of 6 weekly treatments is usual.
- Smoking pack-years
A measure of exposure to cigarette smoke that is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked. For example, 1 pack-year is equal to smoking 20 cigarettes (1 pack) per day for 1 year or 40 cigarettes per day for half a year.
Less densely packed or 'open' chromatin that is often associated with active transcription.
- Field change
A process by which molecular alterations are accumulated within a large tissue area in response to carcinogenic stimuli.
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Knowles, M., Hurst, C. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15, 25–41 (2015). https://doi.org/10.1038/nrc3817
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