Reappraisal of clinicopathological relevance of RON expression in upper tract urothelial carcinoma

Purpose: Aberrant activation and cross-talk of recepteur d’origine nantais (RON) and epidermal growth factor receptor (EGFR) family receptors have been reported in several human malignancies, including urinary bladder. However, the clinical significance of RON and EGFR family receptors in patients with upper tract urothelial carcinoma (UTUC) remains unexplored. Materials and methods: Immunohistochemical staining for RON, EGFR family member was performed on serial sections of archival tissue specimens from 124 patients with UTUC who underwent nephroureterectomy plus bladder cuff resection. Clinicopathological characteristics were retrospectively reviewed, and cancer-specific survival was determined by medical records. The associations between clinicopathological variables, expression status of receptors, and cancer-specific survival were analyzed. T24 cell sublines and one published Cornell’s series were utilized for gene set enrichment analysis. Results: With a median follow-up duration of 50 months (range: 1–177 months), 41 UTUC-related deaths were recorded. RON, EGFR, human epidermal growth factor receptor 2 (HER2/neu), and human epidermal growth factor receptor 3 (HER3) expressions were positive in 45 of 124 (36.3%), 20 of 124 (16.1%), 13 of 96 (13.5%), and 26 of 96 (27.1%) tumors, respectively. Both univariate and multivariate Cox regression analyses showed that stage (hazard ratio 1.85; 95% confidence interval, 1.13–3.00; P = 0.014) and RON expression (hazard ratio, 1.95; 95% confidence interval, 1.04–3.66; P = 0.038) were independent poor prognostic factors for disease-specific overall survival. Gene set enrichment analysis results showed that RON expression predicts gene enrichment with disease metastasis (normalized enrichment score, 1.89, P = 0.008). Conclusion: RON expression was an independent predictor of poor cancer-specific survival. UTUC with RON/HER2 coexpression exhibits the potential of metastatic behavior and the worst outcome.