title: Large-scale analysis of cell cycle regulators in urothelial bladder cancer identifies p16 and p27 as potentially useful prognostic markers.
abstract: OBJECTIVE
  We investigated the value of multiple cell cycle markers for their prognostic impact on overall survival and recurrence-free survival in urothelial carcinoma (UC).
  
  
  METHODS
  A tissue microarray consisting of 99 UCs was evaluated for the expression of p53, p16, p21, p27, cyclin D1, cyclin E , Bcl-2, Ki-67 and PCNA. Statistical analysis was performed applying Kaplan-Meier and Cox regression models using receiver operator characteristic curves for determination of markers' cutoffs.
  
  
  RESULTS
  Expression above the cutoffs of Ki-67, p53 and p27, particularly in high-grade and early-stage UC, was associated with worse overall survival, while expression of p16 indicated a better outcome in low-grade and low-stage tumors. Recurrence-free survival was better in patients with high-grade UC expressing PCNA, p16 and cyclin E, and low-grade UC expressing Bcl-2 above the cutoffs, but worse in all tumors with high Ki-67.
  
  
  CONCLUSIONS
  Cell cycle deregulation in UC is complex and the prognostic value of the various involved proteins should be differentially regarded with respect to this complexity and other tumor characteristics such as grade and stage. Our results point towards the role of p16- and p27-associated pathways in tumor progression and indicate that, by using standardized approaches for tissue antigen expression, evaluation and cutoff determination, single potentially useful prognostic markers could be identified.
authors.affiliation: Institute of Pathology, Medical University of Innsbruck, Innsbruck, Austria. andrea.brunner@i-med.ac.at
authors.forename: Andrea
authors.initials: A
authors.lastname: Brunner
authors.forename: Irmgard
authors.initials: I
authors.lastname: Verdorfer
authors.forename: Martina
authors.initials: M
authors.lastname: Prelog
authors.forename: Christina
authors.initials: C
authors.lastname: Mayerl
authors.forename: Gregor
authors.initials: G
authors.lastname: Mikuz
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D011379:Prognosis; D012372:ROC Curve; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D019459:Urothelium / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050760:Cyclin-Dependent Kinase Inhibitor p27