title: Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.
abstract: BACKGROUND
  Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort.
  
  
  METHODS
  Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, apoptotic protease-activating factor 1 (Apaf-1), Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. "Smoking intensity" quantified the impact of duration and daily frequency of smoking.
  
  
  RESULTS
  Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P < .001). Apaf-1, E-cadherin, and p53 were prognostic for outcome (P = .005, .014, and .032, respectively); E-cadherin remained prognostic following multivariable analysis (P = .040). Combined alterations in all 9 biomarkers were prognostic by univariable (P < .001) and multivariable (P = .006) analysis. A multivariable model that included all 9 biomarkers and smoking intensity had greater accuracy in predicting prognosis than models composed of standard clinicopathological covariates without or with smoking intensity (P < .001 and P = .018, respectively).
  
  
  CONCLUSIONS
  Apaf-1, E-cadherin, and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the 9-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.
authors: Department of Pathology, University of Southern California, Los Angeles, California, USA.
authors: Anirban P
authors: AP
authors: Mitra
authors: Jose E
authors: JE
authors: Castelao
authors: Debra
authors: D
authors: Hawes
authors: Denice D
authors: DD
authors: Tsao-Wei
authors: Xuejuan
authors: X
authors: Jiang
authors: Shan-Rong
authors: SR
authors: Shi
authors: Ram H
authors: RH
authors: Datar
authors: Eila C
authors: EC
authors: Skinner
authors: John P
authors: JP
authors: Stein
authors: Susan
authors: S
authors: Groshen
authors: Mimi C
authors: MC
authors: Yu
authors: Ronald K
authors: RK
authors: Ross
authors: Donald G
authors: DG
authors: Skinner
authors: Victoria K
authors: VK
authors: Cortessis
authors: Richard J
authors: RJ
authors: Cote
mesh_terms: D000368:Aged; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D015331:Cohort Studies; D005500:Follow-Up Studies; D006801:Humans; D015141:Los Angeles; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D012907:Smoking; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology / Q000601:surgery
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D014408:Biomarkers, Tumor; D015820:Cadherins; D016159:Tumor Suppressor Protein p53