mTOR Pathway Alterations in Chromophobe Renal Cell Carcinoma (RCC)
R Albadine, L Schultz, J Hicks, AM Demarzo, P Argani, M Carducci, R Pili, GJ Netto. Johns Hopkins University, Baltimore
Background: Dysregulation of mTOR pathway has been demonstrated in several types of malignancies. mTOR pathway activation interacts with effectors of cell cycle progression and ultimately regulates protein translation and cell proliferation. Tumor hypoxia modulates mTOR pathway through HIF1α accumulation. Agents targeting mTOR are in various stages of clinical development. Here, we assess the status of several mTOR pathway components in Chormophobe RCC.
Design: Standard immunohistochemical analysis was performed for PTEN, phos Akt, p27, c-MYC, 4-EBP1, phos S6, and HIF1α using tissue microarrays constructed from 33 primary Chormophobe RCC (60% pT1 and 40% pT2-3) treated at our hospital (2004-2006). Triplicate tumor samples and paired benign renal tissue controls were spotted in every case. Nuclear and or cytoplasmic expression was assessed for each marker as the percentage of positive cells (extent) and intensity of staining. A final H-score was calculated in each tumor as the product of intensity x extent, and was correlated with clinico-pathological parameters.
Results: In our cohort, M:F ratio was 1.13 and mean age at diagnosis was 59.7 years. Mean tumor size was 4.7 cm. Three cases had multifocal disease. Mean length of follow-up was 28 months (range: 2-61). A 97% disease free survival rate was observed during follow up. Chromophobe RCC demonstrated PTEN lack of expression in 19 (57%) cases. We found significantly lower expression levels of p27 (p=0.0000) and higher expression of phos Akt, phos S6,and 4-EBP1 in Chromophobe RCC compared to benign controls (p=0.003, 0.004 and p=0.0000, respectively). Furthermore, both 4-EBP1 and c-MYC expression levels had a positive correlation with pTNM stage (p=0.01 and 0.03, respectively). Interestingly, multifocal tumors demonstrated a higher expression of PTEN, phos Akt, and HIF1α (p<0.04)
Conclusions: We found the expression of several members of mTOR pathway to be significantly altered in Chromophobe RCC. The finding suggest a potential role for mTOR pathway in the oncogenesis of this histologic type of RCC. Analysis in a larger cohort is warranted.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 135, Tuesday Morning