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Promoter Hypermethylation Identifies Progression Risk in Bladder Cancer

Authors' Affiliations: ¹ Institute of Cancer Studies, ² Academic Urology Unit, ³ Academic Pathology Unit, and ⁴ Department of Automatic Control and Systems Engineering, The University of Sheffield, Sheffield, United Kingdom and ⁵ School of Engineering and Design, Brunel University, West London, United Kingdom

Requests for reprints: James Catto, Academic Urology Unit, K Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, United Kingdom. Phone: 44-114-271-2154; Fax: 44-114-271-2268; E-mail: J.Catto{at}sheffield.ac.uk.

Purpose: New methods to accurately predict an individual tumor behavior are urgently required to improve the treatment of cancer. We previously found that promoter hypermethylation can be an accurate predictor of bladder cancer progression, but it is not cancer specific. Here, we investigate a panel of methylated loci in a prospectively collected cohort of bladder tumors to determine whether hypermethylation has a useful role in the management of patients with bladder cancer.

Experimental Design: Quantitative methylation-specific PCR was done at 17 gene promoters, suspected to be associated with tumor progression, in 96 malignant and 30 normal urothelial samples. Statistical analysis and artificial intelligence techniques were used to interrogate the results.

Results: Using log-rank analysis, five loci were associated with progression to more advanced disease (RASSF1a, E-cadherin, TNFSR25, EDNRB, and APC; P < 0.05). Multivariate analysis revealed that the overall degree of methylation was more significantly associated with subsequent progression and death (Cox, P = 0.002) than tumor stage (Cox, P = 0.008). Neuro-fuzzy modeling confirmed that these five loci were those most associated with tumor progression. Epigenetic predictive models developed using artificial intelligence techniques identified the presence and timing of tumor progression with 97% specificity and 75% sensitivity.

Conclusion: Promoter hypermethylation seems a reliable predictor of tumor progression in bladder cancer. It is associated with aggressive tumors and could be used to identify patients with either superficial disease requiring radical treatment or a low progression risk suitable for less intensive surveillance. Multicenter studies are warranted to validate this marker.