Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression

Abstract

Purpose: In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma.

Materials and methods: We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score.

Results: PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1- BAP1+ in 48.6%, PBRM1+ BAP1- in 8.7% and PBRM1- BAP1- in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor was significantly lower than expected (actual 1.8% vs expected 5.3%, p <0.0001). Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1- BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1- and PBRM1- BAP1- tumors (HR 3.25 and 5.2, respectively, each p <0.001). PBRM1 and BAP1 expression did not add independent prognostic information to the SSIGN score.

Conclusions: PBRM1 and BAP1 expression identified 4 clinical subgroups of patients with clear cell renal cell carcinoma who had divergent clinical outcomes. The clinical value of these biomarkers will be fully realized when therapies targeting pathways downstream of PBRM1 and BAP1 are developed.

Keywords: biological markers; carcinoma; genes; kidney; mortality; renal cell; tumor suppressor.

Figure 1

RCC specific outcomes in patients by PBRM1 expression. A, patients with PBRM1− tumors were at increased risk for metastasis vs patients with PBRM1+ tumors (HR 1.46, p = 0.001). B, after adjusting for age patients with PBRM1− tumors were not at increased risk for RCC death vs patients with PBRM1+ tumors (HR 1.08, p = 0.54).

Figure 2

IHC reveals molecular heterogeneity of PBRM1 and BAP1 in same ccRCC sample. Positive stained nuclei in BAP1− or PBRM1− tumors correspond to stromal or inflammatory cells. These nuclei were typically smaller than tumor nuclei and showed more condensed chromatin. A, tumor with 2 areas, including 1 BAP1+ PBRM1− area and 1 BAP1− PBRM1+ area. B, tumor with loss of BAP1 and PBRM1 throughout. Scale bars indicate 100 μm. Insets, reduced from X400.

Figure 3

RCC specific outcomes in patients by PBRM1 and BAP1 protein expression. PBRM1+ BAP1+ served as HR referent. A, metastasis risk significantly differed among 4 cohorts. For PBRM1− BAP1+ HR 1.91, for PBRM1+ BAP1− HR 3.16 and for PBRM1− BAP− HR 4.94 (each p <0.00001). B, risk of RCC death significantly differed among 4 cohorts. For PBRM1− BAP1+ HR 1.39 (p = 0.03), for PBRM1+ BAP1+ HR 3.25 (p <0.00001) and for PBRM1− BAP1− HR 5.22 (p <0.00001).