BAP1 Loss Results in mTORC1 Activation 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). Mammalian target of rapamycin complex 1 (mTORC1) controls key cellular processes such as survival and proliferation, and is often dysregulated in ccRCC. Drugs targeting mTORC1 pathway are approved for clinical use. We undertook this study to ascertain if expression of mTORC1 pathway members in ccRCC correlates with BAP1 loss.
Design: Immunohistochemistry (IHC) was performed for p-S6, mTOR, p-4E-BP1, PI3 Kinase, p-AKT, HIF1α, Raptor, 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. Cytoplasmic and/or nuclear (HIF1α) expression was assessed for all other marker as the percentage of positive cells (0-3) and intensity of staining (0-3). A final Histo-score was calculated in each tumor as the product 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 p-S6 (p=0.00000031), p-4E-BP1 (p=0.0011), p-AKT (p=0.000015), and decreased HIF1α (p=0.0174) expression.
Conclusions: The significant association of strong p-S6, and p-4E-BP1 immunoexpression with BAP1 loss suggests that the rapamycin-sensitive mTORC1 pathway is hyperactive in these tumors and therefore drugs that inhibit this pathway may be of therapeutic benefit in this novel subgroup of ccRCC patients. Since nucleolar size, the main determinant of Fuhrman grading, is controlled by mTORC1, our data suggests that BAP1 loss may be a key determinant of ccRCC behavior.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 92, Tuesday Morning