title: FGFR3 mutations and a normal CK20 staining pattern define low-grade noninvasive urothelial bladder tumours.
abstract: OBJECTIVE
  Molecular markers superior to conventional clinicopathologic parameters are needed to predict disease courses in bladder cancer patients. In this study, we investigated four markers (Ki-67, TP53, CK20, FGFR3) in primary urothelial bladder tumours and compared them with traditional pathologic features.
  
  
  METHODS
  Tissue microarrays were used to analyse CK20, TP53, and Ki-67 expression immunohistochemically in 255 unselected patients. FGFR3 mutations were detected by SNaPshot analysis.
  
  
  RESULTS
  Abnormal CK20 expression was strongly associated with higher tumour grades and stages (p < 0.001); however, 65% of pTa tumours revealed an abnormal CK20 pattern. In the group of pTaG1 tumours, 59% presented with an abnormal CK20 pattern, whereas 82% carried the FGFR3 mutation. In the group of bladder tumours with normal CK20 pattern, the FGFR3 gene was mutated in 89%, whereas a mutated FGFR3 gene was found in only 37% of cases with abnormal CK20 expression (p < 0.001). All markers proved to be strong predictors of disease-specific survival in univariate studies. However, in multivariate analyses they were not independent from classical pathologic parameters. None of the molecular markers was significantly associated with tumour recurrence.
  
  
  CONCLUSIONS
  Dysregulation of CK20 expression is an early event in the carcinogenesis of papillary noninvasive bladder cancer, but occurs later than FGFR3 mutations. The group of low-grade noninvasive papillary tumours is defined by the presence of an FGFR3 mutation and a normal CK20 expression pattern.
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Johanna M M
authors.initials: JM
authors.lastname: van Oers
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: Stefan
authors.initials: S
authors.lastname: Denzinger
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Elke
authors.initials: E
authors.lastname: Rosskopf
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Monika
authors.initials: M
authors.lastname: Klinkhammer-Schalke
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.forename: Theodorus H
authors.initials: TH
authors.lastname: van der Kwast
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053554:Keratin-20 / Q000235:genetics* / Q000378:metabolism; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D053554:Keratin-20; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3