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DNA methylation-based biomarkers in bladder cancer

Nature Reviews Urology volume 10, pages 327–335 (2013)Cite this article

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Abstract

Urinary bladder cancer is the fifth most common cancer in the Western world. Increasing evidence has shown that DNA methylation in bladder cancer is expansive and is implicated in pathogenesis. Furthermore, distinct methylation patterns have been identified between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), as well as between FGFR3-mutant and wild-type tumours. Given these distinctions in expression, methylated genes have been proposed as diagnostic and prognostic biomarkers for patients with bladder cancer. Indeed, several studies have revealed that methylated genes—including CDH1, FHIT, LAMC2, RASSF1A, TIMP3, SFRP1, SOX9, PMF1 and RUNX3—are associated with poor survival in patients with MIBC. Further validation of these markers for prognostication as well as surveillance (of patients with NMIBC) is required. Validated markers for progression, diagnosis, survival and BCG response will contribute to clinical decision-making and individualized treatment.

Key Points

  • DNA methylation in bladder tumours might be an early event in cancer pathogenesis

  • Distinct methylation patterns have been identified between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), as well as between FGFR3-mutant and wild-type tumours

  • The methylation of several genes involved in processes—such as cell cycle arrest, transcription, cell–cell adhesion, apoptosis and cellular differentiation—have been associated with progression in NMIBC

  • Methylation of the CDH1, FHIT, LAMC2, RASSF1A, TIMP3, SFRP1, SOX9, PMF1 and RUNX3 genes is associated with poor survival in patients with MIBC

  • Methylation of SYNPO2 is associated with resistance to BCG treatment in different cohorts of patients with T1G3 bladder cancer

  • DNA methylation might represent a potential target for future therapies in the bladder cancer setting

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Figure 1: DNA methylation in normal and cancer cells.
Figure 2: Methylated genes implicated in predicting bladder tumour disease course.

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Acknowledgements

The authors are supported by a research grant from Erasmus MC (Mrace) and a grant from the Dutch Cancer Society (EMCR 2007-3863).

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  1. Department of Pathology, Erasmus MC, P. O. Box 2040, Rotterdam, 3000 CA, The Netherlands

    Raju Kandimalla, Angela A. van Tilborg & Ellen C. Zwarthoff

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R. Kandimalla researched the data for the article. All authors discussed the article's content, wrote the manuscript and edited it before submission.

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Correspondence to Ellen C. Zwarthoff.

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Supplementary information

Supplementary Table 1

Overview of all DNA methylation markers in bladder cancer (reported up to April 2012). (DOC 465 kb)

Supplementary Table 2

Urine methylation markers in bladder cancer (DOC 212 kb)

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Kandimalla, R., van Tilborg, A. & Zwarthoff, E. DNA methylation-based biomarkers in bladder cancer. Nat Rev Urol 10, 327–335 (2013). https://doi.org/10.1038/nrurol.2013.89

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