Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas

Ano de Publicação: 2013

AUTORIA

Alcides Chaux MDa,b, Roula Albadine MDa,c, Luciana Schultz MDa,

Jessica Hicks MSa, Michael A. Carducci MDd,e, Pedram Argani MDa,

Mohamad Allaf MDd,e, George J. Netto MDa,d,e,⁎

aDepartment of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

bOffice of Scientific Research, Norte University, Asunción, Paraguay

cDepartment of Pathology and Cellular Biology, Faculty of Medicine, Universite de Montreal, Montréal,

H3X 3J4, Canada

dDepartment of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

eDepartment of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

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 b .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 b .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 hypoxiainduced

pathway members lacked prognostic significance in our cohort.