Prognostic Significacne of MTORC1 Immunoexpression in Clear Cell (Conventional) Renal Cell Carcinoma.
Payal Kapur, Dinesh Rakheja, Ramy F Yousse, Vitaly Margulis, Wareef Kabbani, Yair Lotan. UT Southwestern Medical Center, Dallas, TX
Background: The mammalian target of rapamycin complex 1 (mTORC1) signaling controls key cellular processes such as survival and proliferation, is dysregulated in many human cancers, and drugs targeting this pathway are in clinical development. We undertook this study to ascertain if clear cell (conventional) renal cell carcinoma (ccRCC) 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 phospho-(Ser235/236)-S6 ribosomal protein (pS6), phospho-(Ser2448)-mTOR (p-mTOR), and mTOR using tissue microarrays constructed from 288 primary ccRCC 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 staining intensity was scored as 0 (absent), 1 (weak), 2 (moderate), or 3 (strong). The percentage of positively staining cells was scored as 0 (none), 1 (<10%), 2 (10-70%), or 3 (>70%). A final Histo-score was calculated in each tumor as the product of intensity and percentage, and was correlated with clinico-pathological parameters and outcome using the nonparametric van der Waerden test. Two-tailed P<0.05 was considered significant.
Results: In our cohort, M:F ratio was 1.48 and mean age at diagnosis was 62 years. Mean tumor size was 5.7 cm. 27 (9%) patients had bilateral tumors, 107 (37%) had high Fuhrman grade (G3-4), 79 (27%) had high pathologic stage (pT3-4), 46 (16%) developed subsequent metastases / recurrence, and 17 (6%) died of the disease. P-S6 staining was weak in 76 (26%) and strong in 61 (21%) cases; p-mTOR was weak in 82 (28%) and strong in 129 (45%) cases; mTOR was weak in 96 (33%) and strong in 60 (21%) cases. Stronger expression of p-S6 was associated with high Fuhrman grade (p<0.0001), high pathologic stage (p=0.0016), and the development of metastases / recurrence (p=0.0478). The staining pattern of all antibodies was essentially similar in nature and consisted of granular cytoplasmic staining.
Conclusions: The significant association of strong p-S6 immunoexpression with higher grade, higher stage, and subsequent development of metastasis / recurrence in ccRCC suggests that the rapamycin-sensitive mTORC1 pathway is hyperactive and therefore an attractive therapeutic target in these tumors.
Category: Genitourinary (including renal tumors)
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 118, Wednesday Morning