Loss of BAP1 and PBRM1 expression in non-clear cell renal cell carcinomas compared to clear cell renal cell carcinomas.

4529 Background: Loss of function mutations in PBRM1 (41-50%) and BAP1(5-15%) are associated with poor outcomes for patients with clear cell renal cell carcinoma (ccRCC) tumors. However, there are no data regarding the prevalence of these mutations in other RCC subtypes (non-ccRCC). We evaluated loss of PBRM1 and BAP1 expression in ccRCC and non-ccRCC tumors using an IHC assay for which negative staining correlates with loss of function mutations. Methods: From our Registry database, we identified 311 and 105 patients treated surgically for ccRCC and non-ccRCC. We performed IHC assays to evaluate PBRM1 and BAP1 protein expression. We classified tumors as BAP1 or PBRM1 negative when tumor cells showed diffuse absence of nuclear staining. We compared loss of expression of these two proteins between ccRCC and non-ccRCC using Fisher’s exact tests. Results: Of the total cohort of 416 patients, we successfully stained BAP1 in 406 (97.5%) and PBRM1 in 372 (89.4%). Of those with successful staining, we further excluded samples with focal negative or weak positive expression of BAP1 (n=59) or PBRM1 (n=55). Thus, we were left with 186 ccRCC and 79 non-ccRCC patient samples that had both BAP1 and PBRM1 available for analysis. We observed BAP1 loss of expression in 9% (17/186) of the ccRCC tumors but only 1% (1/79) of the non-ccRCC tumors (p=0.016). Similarly, we noted loss of expression of PBRM1 in 43% (80/186) of the ccRCC tumors but only 4% (3/79) of the non-ccRCC tumors (p=0.0001). Of note, within the non-ccRCC group, we observed 0% (0/61) papillary tumors and 5% (1/18) chromophobe tumors with loss of BAP1. By comparison, 3% (2/61) of papillary tumors and 1/18 (5%) of chromophobe tumors showed loss of PBRM1 expression. Conclusions: Our data are the first to suggest that loss of function mutations in PBRM1 and BAP1 are less common in non-ccRCC tumors compared to ccRCC. If these findings are independently confirmed, they suggest that while loss of PBRM1 and BAP1 are key events in ccRCC, disruption of other pathways may support tumorigenesis in non-ccRCC subtypes. BAP1/PBRM1 Papillary Chromophobe ccRCC -/- 0 (0%) 0 (0%) 3 (2%) -/+ 0 (0%) 1 (5%) 14 (8%) +/- 2 (3%) 1 (5%) 77 (41%) +/+ 59 (97%) 16 (90%) 92 (49%) 61 18 186