TY - JOUR
T1 - Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas
AU - Chaux, Alcides
AU - Albadine, Roula
AU - Schultz, Luciana
AU - Hicks, Jessica
AU - Carducci, Michael A.
AU - Argani, Pedram
AU - Allaf, Mohamad
AU - Netto, George J.
N1 - Funding Information:
Disclosure: Partially supported by The Brady Urological Institute-Johns Hopkins Medicine Patana Fund for Research. Dr. Alcides Chaux was partially supported by an award granted by the CONACYT (National Council of Science and Technology) dependent of the Presidency of the Republic of Paraguay, as an Active Researcher of Level 1 of the PRONII (National Incentive Program for Researchers).
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/10
Y1 - 2013/10
N2 - Summary Targeted therapy in advanced clear cell renal cell carcinomas (RCC) is now an established modality. The latter is in stark contrast to non-clear cell subtypes. We explored the translational support for the use of antagonists of the mammalian target of rapamycin (mTOR) and the vascular endothelial growth factor pathways in chromophobe RCC. The immunoexpression of PTEN, phos-AKT, phosphorylated S6 (phos-S6), 4EBP1, p27, c-MYC, and HIF-1α was evaluated in 33 patients with chromophobe RCC who were treated by partial/radical nephrectomy without adjuvant therapy. PTEN was lower in tumor than in normal kidney (P <.001), and loss of PTEN expression was found in 67% of the tumors. In tumor tissues, phos-S6 and 4EBP1 were higher than in normal kidney (P ≤.005). Conversely, scores of p27 were lower in tumor than in normal kidney (P <.001). Finally, scores of phos-AKT, c-MYC, and HIF-1α were not significantly different in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 9% and 0%, respectively. Multifocal tumors had higher levels of PTEN, phos-AKT, and HIF-1α (P ≤.01). None of the clinicopathologic variables (age, ethnicity, gender, pT stage, tumor size, multifocality, and positive surgical margins) was associated with outcome. Similarly, none of the tested biomarkers predicted overall mortality, either in unadjusted or adjusted Cox regression models. In summary, our study provides new evidence of dysregulation of the mTOR pathway in chromophobe RCC. Immunohistochemistry for mTOR pathway and hypoxia-induced pathway members lacked prognostic significance in our cohort.
AB - Summary Targeted therapy in advanced clear cell renal cell carcinomas (RCC) is now an established modality. The latter is in stark contrast to non-clear cell subtypes. We explored the translational support for the use of antagonists of the mammalian target of rapamycin (mTOR) and the vascular endothelial growth factor pathways in chromophobe RCC. The immunoexpression of PTEN, phos-AKT, phosphorylated S6 (phos-S6), 4EBP1, p27, c-MYC, and HIF-1α was evaluated in 33 patients with chromophobe RCC who were treated by partial/radical nephrectomy without adjuvant therapy. PTEN was lower in tumor than in normal kidney (P <.001), and loss of PTEN expression was found in 67% of the tumors. In tumor tissues, phos-S6 and 4EBP1 were higher than in normal kidney (P ≤.005). Conversely, scores of p27 were lower in tumor than in normal kidney (P <.001). Finally, scores of phos-AKT, c-MYC, and HIF-1α were not significantly different in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 9% and 0%, respectively. Multifocal tumors had higher levels of PTEN, phos-AKT, and HIF-1α (P ≤.01). None of the clinicopathologic variables (age, ethnicity, gender, pT stage, tumor size, multifocality, and positive surgical margins) was associated with outcome. Similarly, none of the tested biomarkers predicted overall mortality, either in unadjusted or adjusted Cox regression models. In summary, our study provides new evidence of dysregulation of the mTOR pathway in chromophobe RCC. Immunohistochemistry for mTOR pathway and hypoxia-induced pathway members lacked prognostic significance in our cohort.
KW - 4EBP1
KW - AKT
KW - Chromophobe renal cell carcinoma
KW - HIF-1α
KW - PTEN
KW - S6
KW - mTOR
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U2 - 10.1016/j.humpath.2013.05.014
DO - 10.1016/j.humpath.2013.05.014
M3 - Article
C2 - 23953228
AN - SCOPUS:84884418061
SN - 0046-8177
VL - 44
SP - 2323
EP - 2330
JO - Human pathology
JF - Human pathology
IS - 10
ER -