BAP1 Loss Defines a Pathologically Aggressive Subgroup of Clear Cell Renal Cell Carcinoma
Payal Kapur, Alana Christie, Samuel Pena-Llopis, Vitaly Margulis, Yair Lotan, Xian-Jin Xie, James Brugarolas. University of Texas Southwestern Medical Center, Dallas, TX
Background: Clear cell renal cell carcinoma (ccRCC) the most common subtype accounting for 85% of all renal cell carcinomas. Recently mutations in a tumor suppressor gene, BAP1 (BRCA1 associated protein-1) were described to occur frequently in ccRCC. In this study we investigate the clinicopathologic significance of BAP1 loss using immunohistochemical assay that was validated using ccRCC tumor samples with genetically defined BAP1 status as controls.
Design: Immunohistochemistry was performed for BAP1 using tissue microarrays constructs from 433 primary ccRCC treated at our institution with nephrectomy (1998-2008). Duplicate 1.0 mm cores of representative tumor were obtained from each case to construct the tissue microarrays. Any nuclear reactivity was considered positive for BAP1, and in each tumor section lymphocytes, stromal fibroblasts and endothelial cells served as internal positive control cells. BAP1 expression was correlated with pathological parameters using t-test (for continuous variables) and Fisher's exact test (for categorical variables).
Results: In our cohort, M:F ratio was 1.5, mean age at diagnosis was 57 years, and median tumor size was 4.4 cm. Of the 433 ccRCC cases studied, 119 (27%) had high Fuhrman nuclear grade, 109 (23.1 and 2.1 % respectively) were pT3-4, 14 (3.2%) patients had sarcomatoid differentiation and 74 (17.1%) had venous thrombus. Twenty-one of 98 patients that underwent lymph node resection had nodal metastases. BAP1 was negative in 45 (10.4%) and positive in 388 (89.6) tumors. When compared to BAP1 positive tumors, BAP1 loss was significantly associated with larger tumor size (p=0.0010), high Fuhrman grade (p=0.00000048), advanced pT stage (p=0.0266), and presence of venous thrombus (p=0.0354).
Conclusions: This study indicates that ccRCCs with BAP1 loss are associated with aggressive pathologic features. These data provide a basis for subclassification of ccRCC that may provide improved prognostication and treatment stratification that can readily be incorporated in everyday practice.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 187, Tuesday Afternoon