Prognostic Relevance of mTORC1 Pathway Components in Chromophobe Renal Cell Carcinoma
Theresa Kinard, Dinesh Rakheja, Ramy F Youssef, Yair Lotan, Vitaly Margulis, Jessica Sugianto, Payal Kapur. University of Texas Southwestern, Dallas, TX
Background: The mammalian target of rapamycin complex 1 (mTORC1) pathway is dysregulated in many human cancers and agents targeting the mTORC1 are being clinical used. mTORC1 pathway interacts with effectors of cell cycle progression and ultimately regulates protein translation and cell proliferation. We undertook this study to ascertain if chromophobe renal cell carcinoma (ChRCC) demonstrates significant expression of mTORC1 pathway components and if the expression of activated mTORC1 has any prognostic significance.
Design: Standard immunohistochemical analysis was performed for p-S6, p-mTOR, p-4EBP1, HIF-1a, p-AKT, PI3K, PTEN on sections of tissue microarrays constructed from 43 primary ChRCC treated at our hospital with nephrectomy (1998-2008). Duplicate 1.0 mm cores of representative tumor were obtained from each case to construct the tissue microarrays. Cytoplasmic expression was assessed for each marker as the percentage of positive cells (0-3) and intensity of staining (0-3). A final Histo-score was calculated as the product of intensity and percentage and correlated with clinic-pathologic parameters.
Results: In our cohort, M:F ratio was 1.0 and mean age at diagnosis was 55.3 years. Mean tumor size was 7.0 cm. 8 (18.6%) had high pathologic stage (pT3-4), 3 (7.0%) developed metastases/recurrence, and 0 died of disease. Compared to normal proximal renal tubules, we found increased expression of p-S6 in 6 (14.0%) tumors, p-mTOR in 28 (65.1%), p-4EBP1 in 14 (32.6%), HIF-1a in 41 (95.3%), PI3K in 12 (27.9%), and p-AKT in 13 (30.2%). PTEN expression was reduced in 29 (67.4%) tumors. Two tail t-test showed increased expression of p-S6 (P=0.04), p-4EBP1 (P=0.00), and p-AKT (P=0.04) to be significantly associated with higher stage. In addition, there was a trend for higher stage tumors to show higher expression of PI3K (P=0.06).
Conclusions: In this current work in clinically annotated ChRCC where the patients had received no previous treatment, we found that increased expression of pS6, p-4EBP1, p-AKT, and PI3K correlates with higher tumor stage. Our results support consideration of therapeutically targeting PI3K/AKT/mTORC1 pathway in ChRCC.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 153, Monday Morning