High CDKN2A/p16 and Low FGFR3 Expression Predict Progressive Potential of Stage pT1 Urothelial Bladder Carcinoma

Identifying pT1 bladder cancer with high risk for progression remains a challenge. Aberrations in cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 and fibroblast growth factor receptor 3 (FGFR3) expression are the most common in urothelial bladder cancer. In the study at hand, we could show that high CDKN2A/p16 mRNA expression is associated with the luminal subtype and high CDKN2A/p16 as well as low FGFR3 mRNA expression are associated with worse progression-free survival. Background: A recent study on the comprehensive genomic profile of advanced urothelial bladder cancer (UBC) showed cyclin-dependent kinase inhibitor 2A (CDKN2A) and fibroblast growth factor receptor 3 (FGFR3) as the most often clinically relevant genomic alterations. Therefore, the prognostic role of FGFR3 and CDKN2A/p16 for pT1 UBC was studied. Patients and Methods: Clinical data and formal in-fixed paraffin-embedded tissues of pT1 UBC treated with an organ-preserving approach was analyzed retrospectively. Total RNA was isolated using commercial RNA extraction kits and mRNA expression of CDKN2A/p16 and FGFR3 was measured using single step reverse transcription quantitative real time polymerase chain reaction using RNA-specific TaqMan assays. Results: Data from 296 patients (79.4% male; median age: 72 years) could be used for the final evaluation. Spearman correlation revealed a statistically significant negative correlation between mRNA expression of CDKN2A/p16 and FGFR3. There was a positive correlation between CDKN2A/p16 and G3 tumors (rho = 0.1875; P = .0012) and associated carcinoma in situ (rho = 0.1703, P = .0033) and a negative correlation between FGFR3 and these factors (rho = -0.2791, P < .0001 and rho = -0.2182, P = .0002). High CDKN2A/p16 expression (>= 38.04) and low FGFR3 expression (<39.14) were statistically significantly associated with worse progression-free survival (PFS; P = .0194 and P = .0089). Multivariate Cox regression analysis could identify patients with low FGFR3 and high CDKN2A/p16 expression (log rank (LR)chi(2) = 10.69; P = .0048) as well as tumor size >= 3 cm (LR chi(2) = 6.03; P = .0141) as independent predictors for PFS. Conclusion: High expression of CDKN2A/p16 and low expression of FGFR3 show a correlation with established prognostic features for non-muscle-invasive bladder cancer and can predict progression of stage pT1 UBC.