title: Promoter hypermethylation identifies progression risk in bladder cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Cancer Studies, Academic Urology Unit, Academic Pathology Unit, and Department of Automatic Control and Systems Engineering, The University of Sheffield, Sheffield, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Yates
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Rehman
authors.forename: Maysam F
authors.initials: MF
authors.lastname: Abbod
authors.forename: Mark
authors.initials: M
authors.lastname: Meuth
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Derek A
authors.initials: DA
authors.lastname: Linkens
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: James W F
authors.initials: JW
authors.lastname: Catto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D017143:Fuzzy Logic; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012680:Sensitivity and Specificity; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor