title: Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR.
abstract: BACKGROUND
  Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade.
  
  
  METHODS
  We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain.
  
  
  RESULTS
  Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio=7.4 (95% confidence interval: 3.4-15.9), P<0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing.
  
  
  CONCLUSIONS
  Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Skejby, Denmark. lars@ki.au.dk
authors.forename: L
authors.initials: L
authors.lastname: Dyrskjøt
authors.forename: T
authors.initials: T
authors.lastname: Reinert
authors.forename: A
authors.initials: A
authors.lastname: Novoradovsky
authors.forename: T C M
authors.initials: TC
authors.lastname: Zuiverloon
authors.forename: W
authors.initials: W
authors.lastname: Beukers
authors.forename: E
authors.initials: E
authors.lastname: Zwarthoff
authors.forename: N
authors.initials: N
authors.lastname: Malats
authors.forename: F X
authors.initials: FX
authors.lastname: Real
authors.forename: U
authors.initials: U
authors.lastname: Segersten
authors.forename: P-U
authors.initials: PU
authors.lastname: Malmström
authors.forename: M
authors.initials: M
authors.lastname: Knowles
authors.forename: C
authors.initials: C
authors.lastname: Hurst
authors.forename: J
authors.initials: J
authors.lastname: Sorge
authors.forename: M
authors.initials: M
authors.lastname: Borre
authors.forename: T F
authors.initials: TF
authors.lastname: Orntoft
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D018581:Technology Transfer; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology