title: Dysregulation of β-catenin is an independent predictor of oncologic outcomes in patients with clear cell renal cell carcinoma.
abstract: OBJECTIVE
  Epithelial-to-mesenchymal transition is thought to have a crucial role in cancer progression and metastatic egress. We evaluated the association of β-catenin, an important mediator of epithelial-to-mesenchymal transition, with pathological parameters and oncologic outcomes in patients with clear cell renal cell carcinoma.
  
  
  METHODS
  Immunohistochemical staining was performed for β-catenin on tissue microarrays of patients with nonmetastatic clear cell renal cell carcinoma. Membranous and cytoplasmic expression patterns were assessed separately. β-Catenin was considered dysregulated if membranous as well as cytoplasmic expression was abnormal. Groups were compared based on normal vs dysregulated β-catenin. Survival probabilities were assessed by the Kaplan-Meier method. Cox proportional hazard models were used to identify predictors of oncologic outcomes.
  
  
  RESULTS
  Included in the study were 406 patients with a median followup of 58 months. Of the patients 52 (12.8%) and 25 (6.2%) experienced recurrence and died of clear cell renal cell carcinoma, respectively. β-Catenin was dysregulated in 70 patients (17.2%). Dysregulation was uniformly associated with adverse pathological features, including advanced T stage, larger tumor diameter, nodal positivity, higher Fuhrman grade, tumor thrombus, sarcomatoid features, necrosis and lymphovascular invasion (each p<0.001). Patients with dysregulated β-catenin had inferior recurrence-free and cancer specific survival (each p<0.001). On multivariate analysis adjusting for tumor stage, nodal status and grade dysregulation was an independent predictor of recurrence-free and cancer specific survival (HR 2.2, 95% CI 1.2-3.9, p=0.008 and HR 2.4, 95% CI 1.1-5.6, p=0.044, respectively).
  
  
  CONCLUSIONS
  Dysregulation of β-catenin may be an important phenomenon in clear cell renal cell carcinoma carcinogenesis. These findings support further study of β-catenin, and systematic assessment of β-catenin and epithelial-to-mesenchymal transition in clear cell renal cell carcinoma.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, University of Muenster Medical Center, Muenster, Germany.
authors.forename: Laura-Maria
authors.initials: LM
authors.lastname: Krabbe
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Westerman
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bagrodia
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Bishoy A
authors.initials: BA
authors.lastname: Gayed
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Oussama M
authors.initials: OM
authors.lastname: Darwish
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Ahmed Q
authors.initials: AQ
authors.lastname: Haddad
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Dina
authors.initials: D
authors.lastname: Khalil
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Vitaly.margulis@utsouthwestern.edu.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Margulis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D051176:beta Catenin
keywords: beta catenin; carcinogenesis; carcinoma; epithelial-mesenchymal transition; kidney; renal cell