BAP1 Loss and TFE3 Immunoexpression in High-Grade Clear Cell Renal Cell Carcinoma

Native nuclear TFE3 expression occurs in conventional clear cell renal cell carcinoma (ccRCC) lacking TFE3 rearrangement. Because BAP1 loss is associated with mTORC1 activation and metabolic stress that promote MiT/TFE nuclear translocation, we examined whether BAP1 loss is associated with native TFE3 expression in high-grade ccRCC.

We assembled a retrospective, multi-institutional cohort of 350 high-grade (WHO/ISUP grade 3-4) ccRCC from four centers, with central BAP1, TFE3, and GPNMB immunohistochemistry on tissue microarrays. The pre-specified primary endpoint was association of BAP1 loss with TFE3 expression and tested by center-stratified Cochran-Mantel-Haenszel analysis. BAP1 loss was identified in 84/350 (24.0%), nuclear TFE3 in 43/350 (12.3%), and GPNMB in 21/350 (6.0%). TFE3 positivity was enriched in BAP1-deficient tumors (22.6% vs 9.0%; common odds ratio 3.80, 95% CI 1.88-7.68, p = 0.0001), consistently across cohorts (Breslow-Day p = 0.13), and BAP1 loss remained the only independent predictor of TFE3 expression on multivariable analysis (adjusted OR 3.00, p = 0.001). GPNMB was absent in 40 of 43 (93%) TFE3-positive tumors and in 18 of 19 BAP1-loss/TFE3-positive tumors.

Native TFE3 expression is significantly and independently enriched in BAP1-deficient high-grade ccRCC but is not accompanied by GPNMB, distinguishing it from translocation RCC. Recognising this pattern, and using GPNMB as a discriminator, avoids misclassifying conventional, frequently BAP1-deficient ccRCC as Xp11 translocation RCC.