title: Activation of extracellular regulated kinases (ERK1/2) predicts poor prognosis in urothelial bladder carcinoma and is not associated with B-Raf gene mutations.
abstract: OBJECTIVE
  The analysis of the presence of B-Raf gene mutations in relation to ERK1/2 activation in bladder urothelial carcinoma (UC), in order to determine their potential role in tumour aggressiveness and patients' survival.
  
  
  METHODS
  Polymerase chain reaction-single strand confirmation polymorphism (PCR-SSCP) and sequencing analysis were used for B-Raf gene mutation detection. pERK1/2 and FGFR3 expression were examined by immunohistochemistry in 152 and 116 primary UCs, respectively.
  
  
  RESULTS
  None of the cases displayed mutations in exon 15 of B-Raf gene. Nuclear or cytoplasmic pERK immunoreactivity was displayed in 99.3% and 96.7% of cases, respectively. pERK nuclear expression increased with histological grade and with T-category. Nuclear and cytoplasmic pERK expression was unrelated to FGFR3 expression. In univariate survival analysis of muscle-invasive carcinomas, advanced T-category and higher pERK nuclear expression (p = 0.018) adversely affected survival. However, multivariate analysis in non-invasive as well as in muscle-invasive carcinomas selected only T-category as a significant prognosticator.
  
  
  CONCLUSIONS
  Our findings suggest that elevated pERK expression occurs in UCs in the absence of B-Raf mutations and is not correlated with FGFR3 over-expression. Moreover, it implicates ERK activation in the acquisition of a more aggressive phenotype. However, the assessment of pERK1/2 expression does not seem to add to the prognostic information provided by classical prognosticators.
authors.affiliation: Department of Pathology, Medical School, National and Kapodistrian University of Athens, Goudi, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karlou
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Saetta
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.forename: Pollyanthi
authors.initials: P
authors.lastname: Papanastasiou
authors.forename: Evmorfia
authors.initials: E
authors.lastname: Boltetsou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Isaiadis
authors.forename: Petros
authors.initials: P
authors.lastname: Pavlopoulos
authors.forename: Irene
authors.initials: I
authors.lastname: Thymara
authors.forename: Euphemia
authors.initials: E
authors.lastname: Thomas-Tsagli
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3