title: Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study.
abstract: OBJECTIVE
  Clinically useful molecular markers predicting the clinical course of patients diagnosed with non-muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression.
  
  
  METHODS
  We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome.
  
  
  RESULTS
  Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of T(a) or T(1) tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis.
  
  
  CONCLUSIONS
  This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non-muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.
authors.affiliation: Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.forename: Karsten
authors.initials: K
authors.lastname: Zieger
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hurst
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kotwal
authors.forename: Margaret
authors.initials: M
authors.lastname: Knowles
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.forename: Manuel
authors.initials: M
authors.lastname: de la Torre
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wester
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.forename: Dimitri
authors.initials: D
authors.lastname: Vordos
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caillault
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.forename: Anne-Mette K
authors.initials: AM
authors.lastname: Hein
authors.forename: Jens L
authors.initials: JL
authors.lastname: Jensen
authors.forename: Klaus M E
authors.initials: KM
authors.lastname: Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor