Dysregulation of β-Catenin is an Independent Predictor of Oncologic Outcomes in Patients with Clear Cell Renal Cell Carcinoma

Abstract

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. 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. 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). 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.