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Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet?

Nature Reviews Urology volume 9, pages 41–51 (2012)Cite this article

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Abstract

The unprecedented advances in cancer genetics and genomics are rapidly affecting the clinical management of solid tumors. Molecular diagnostics are now an integral part of routine clinical management for patients with lung, colon, and breast cancer. In sharp contrast, molecular biomarkers have been largely excluded from current management algorithms for urologic malignancies. The need for new treatment options that can improve upon the modest outcomes currently associated with muscle-invasive bladder cancer is evident, and validated prognostic molecular biomarkers that can help clinicians to identify patients in need of early, aggressive management are lacking. Robust predictive biomarkers that are able to forecast and stratify responses to emerging targeted therapies are also needed.

Key Points

  • Molecular genetic evidence supports the existence of two distinct pathogenetic pathways for bladder cancer development, corresponding to two distinct biological and clinical phenotypes: non-muscle-invasive and muscle-invasive urothelial carcinoma

  • Disruption to the PI3K–AKT–mTOR pathway and alterations in the tyrosine kinase receptor gene FGFR3 and the oncogene HRAS are associated with non-muscle-invasive bladder cancer

  • The main genetic alterations underlying muscle-invasive bladder cancer involve tumor suppressor genes encoding proteins that regulate cell cycle and apoptosis pathways, including TP53, CDKN2A, CCND1, CDKN1B, and RB1

  • Delineation of the molecular pathways involved in bladder oncogenesis has fueled the quest for much-needed prognostic biomarkers, new targeted therapies, and markers of therapy response

  • A 'molecular grade' (based on FGFR3 and MIB1 expression) and a multitarget fluorescence in situ hybridization (FISH) assay have both achieved sufficient validation to be included in prospective multi-institutional trials

  • A panel of multiple cell cycle control markers—TP53, CDKN1B, CDKN1A, CDKN2A, CCND1, and RBL1—offers superior prognostic power over single marker approaches, and merits further rigorous prospective validation

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Figure 1: The divergent molecular pathways of oncogenesis in non-muscle-invasive and muscle-invasive bladder cancers.
Figure 2: Possible interactions between Ras–MAPK, JAK–STAT, and PI3K–AKT–mTOR signaling pathways associated with early oncogenesis in noninvasive papillary urothelial neoplasms.
Figure 3: Receptor tyrosine kinase (EGFR, Ras, MAP2K, and MAPK) and cell cycle regulator (p14, p16, p53, p21, cyclin D1, cyclin E, and pRb1) pathways in urothelial carcinoma.

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    George J. Netto

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Netto, G. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet?. Nat Rev Urol 9, 41–51 (2012). https://doi.org/10.1038/nrurol.2011.193

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