BAP1 Loss Results in Cell Cycle Dysregulation and Increased Proliferation in 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: Mutations in BAP1 (BRCA1 associated protein-1), a tumor suppressor gene were recently described to occur in 15% of Clear Cell Renal Cell Carcinoma (ccRCC). Ki-67, a marker of proliferation has been shown to be associated with aggressive biological behavior in patients with ccRCC. Cyclins (cyclin D1) and cyclin dependent kinase inhibitors (p16, p21, p27, p57) have been implicated in various stages of carcinogenesis. We sought to investigate the role of cell cycle regulators in ccRCC with BAP1 loss.
Design: Immunohistochemistry (IHC) was performed for Ki-67, p53, cyclin D1, p21, p27, p16, p57, and BAP1 using tissue microarrays constructed 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. Nuclear expression was assessed for all other marker as the percentage of positive cells (0-100) and intensity of staining (0-3). A final Histo-score was calculated in each tumor as the sum of intensity and percentage, and was correlated with BAP1 immunoexpression using t- test.
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. 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 increased Ki-67 (p=0.0001), and decreased p27 (p=0.0006), p16 (p=0.0169), p57 (p=6.1x10-15), and cyclin D1 (p=0.0344) immunoexpression.
Conclusions: In summary, our study provides evidence of dysregulation of cell cycle regulators in ccRCC with BAP1 loss resulting in increased cell proliferation. We postulate that BAP1 loss results in alteration of cell cycle regulators resulting in increase cell proliferation and aggressive tumor behavior.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 91, Tuesday Morning