title: Cell-cycle control in urothelial carcinoma: large-scale tissue array analysis of tumor tissue from Maine and Vermont.
abstract: BACKGROUND
  Cell-cycle proteins are important predictive markers in urothelial carcinoma but may also exhibit exposure-specific heterogeneity.
  
  
  METHODS
  Tumor tissue from 491 bladder cancer cases enrolled in the Maine and Vermont component of the New England Bladder Cancer Study was assembled as tissue microarrays and examined for aberrant expression of p53, p63, p16, cyclin D1, Rb, and Ki-67. The association between expression and histopathology, demographics, and cigarette smoking was examined using χ(2) tests, multivariable Poisson, and multinomial regression models.
  
  
  RESULTS
  We found that overexpression of p53 and Ki-67 was associated with high-stage/grade tumors [relative risk (RR), 1.26; P(trend) = 0.003; and RR, 3.21; P(trend) < 0.0001, respectively], whereas expression of p63 and p16 was decreased in high-stage/grade tumors (RR, 0.52; P(trend) < 0.0001; and RR, 0.88; P(trend) = 0.04, respectively). No significant aberrations of cell-cycle proteins were identified using various smoking variables and multiple statistical models.
  
  
  CONCLUSIONS
  The results of this population-based study of histologically confirmed urothelial carcinomas show significant aberration of cell-cycle proteins p53, p63, p16, and Ki-67, but not Rb or cyclin D1. p53 showed the most significant heterogeneity with respect to tumor stage and grade, especially when stratified for different staining intensities using novel digital image analysis techniques. Our findings do not support that smoking modifies expression of cell-cycle proteins.
  
  
  CONCLUSIONS
  Our study shows significant heterogeneity in the expression of key cell-cycle proteins that are associated with disease progression in bladder cancer. Further studies may lead to the identification of biomarkers and their multiplexed interactions as useful prognostic and therapeutic targets.
authors: Division of Cancer Epidemiology and Genetics, Science Applications International Corporation-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD, USA.
authors: Petra
authors: P
authors: Lenz
authors: Ruth
authors: R
authors: Pfeiffer
authors: Dalsu
authors: D
authors: Baris
authors: Alan R
authors: AR
authors: Schned
authors: Mikiko
authors: M
authors: Takikita
authors: M Cristina
authors: MC
authors: Poscablo
authors: Molly
authors: M
authors: Schwenn
authors: Alison
authors: A
authors: Johnson
authors: Michael
authors: M
authors: Jones
authors: Masatoshi
authors: M
authors: Kida
authors: Kenneth P
authors: KP
authors: Cantor
authors: Nathaniel
authors: N
authors: Rothman
authors: Debra T
authors: DT
authors: Silverman
authors: Stephen M
authors: SM
authors: Hewitt
authors: Lee E
authors: LE
authors: Moore
mesh_terms: D000328:Adult; D000368:Aged; D002453:Cell Cycle; D019938:Cyclin D1 / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008281:Maine; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D046888:Tissue Array Analysis / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000473:pathology*; D014707:Vermont
chemical_list: C530104:CCND1 protein, human; C000614131:CDKN2A protein, human; C081876:CKAP4 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1