BAP1 and PBRM1 Loss Is Associated with Aggressive Clinicopathological Features in Clear Cell Renal Cell Carcinoma:...

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is a biologically heterogeneous disease. Beyond VHL inactivation, alterations in chromatin remodeling genes BAP1 and PBRM1 define distinct tumor phenotypes with prognostic implications. We sought to characterize the clinicopathological features and oncological outcomes associated with IHC-defined loss of these markers in a contemporary surgical cohort. Methods: We retrospectively analyzed 214 patients undergoing partial or radical nephrectomy for ccRCC (2010-2021). Loss of BAP1 and PBRM1 expression was assessed by automated immunohistochemistry. Tumors with retained expression were classified as wild-type and compared with those showing loss of at least one marker. Survival outcomes were evaluated using Kaplan-Meier analysis, multivariable Cox models, and Restricted Mean Survival Time (RMST). Results: IHC-defined loss was identified in 19 patients (8.9%): BAP1 in 12 (5.6%) and PBRM1 in 7 (3.3%). Tumors with IHC-defined loss showed more aggressive features, including larger size (7.7 vs. 4.7 cm; p = 0.009), higher necrosis (36.8% vs. 18.5%; p = 0.050), and more advanced stage (pT3-pT4: 47.4% vs. 16.4%; p < 0.001). Kaplan-Meier analysis demonstrated significantly worse survival outcomes in the IHC-loss group across all endpoints (p ≤ 0.011). RMST analysis at 60 months confirmed significantly worse outcomes across all endpoints (p ≤ 0.005). Conclusions: Loss of BAP1 or PBRM1 identifies a biologically aggressive ccRCC subset with worse oncological outcomes. IHC-based molecular profiling is a practical and accessible tool for risk stratification in surgically treated ccRCC.