title: Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival: validatory study of two independent patient cohorts.
abstract: BACKGROUND
  Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guérin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts.
  
  
  METHODS
  Immunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS).
  
  
  RESULTS
  Ezrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression.
  
  
  CONCLUSIONS
  The results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.
authors.forename: Gustav
authors.initials: G
authors.lastname: Andersson
authors.forename: Christoffer
authors.initials: C
authors.lastname: Wennersten
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaber
authors.forename: Karolina
authors.initials: K
authors.lastname: Boman
authors.forename: Björn
authors.initials: B
authors.lastname: Nodin
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlén
authors.forename: Ulrika
authors.initials: U
authors.lastname: Segersten
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.affiliation: Department of Clinical Sciences, Oncology and Pathology, Lund University, Skåne University Hospital, Lund 221 85, Sweden. karin.jirstrom@med.lu.se.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D015996:Survival Rate; D013548:Sweden; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality*; D000099149:Ezrin
chemical_list: D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D000099149:Ezrin