title: Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma.
abstract: OBJECTIVE
  We determined whether the combined expression of p53, p21, p27 and pRB is associated with outcomes of patients with nonmuscle invasive bladder transitional cell carcinoma.
  
  
  METHODS
  Immunohistochemical staining for p53, p21, p27 and pRB was performed on archival bladder specimens from 9 normal controls and 74 patients who underwent transurethral bladder tumor resection for Ta, Tis and/or T1 transitional cell carcinoma.
  
  
  RESULTS
  Normal urothelium had wild type status of p53, pRB, p21 and p27. p53 expression was altered in 34% of patients with transitional cell carcinoma, pRB in 39%, p21 in 35% and p27 in 47%. When analyzed separately, p53, pRB and p21 were each independently associated with tumor progression. Combination of biomarkers stratified patients into statistically significantly different risk groups for disease recurrence and progression. When tumor stage and grade were modeled with all 4 biomarkers, p53 and p27 were the sole independent predictors of disease recurrence and progression. After controlling for the effects of tumor grade and stage, the incremental number of altered biomarkers was associated with an increased risk of bladder cancer recurrence (p for trend = 0.011) and progression (p for trend = 0.005). The risk ratio for disease recurrence and progression increased incrementally with the number of biomarkers altered.
  
  
  CONCLUSIONS
  Combinations of p53, pRB, p21 and p27 had cooperative/synergistic effects stratifying patients into different risk groups. Higher total numbers of altered biomarkers were independently associated with an increased risk of disease progression and death. Prospective trials are necessary to usher bladder cancer management into the age of molecular biomarkers.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA. shahrokh.shariat@UTSouthwestern.edu
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D016160:Retinoblastoma Protein / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27