title: Dysregulation of the mammalian target of rapamycin pathway in chromophobe renal cell carcinomas.
abstract: 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.
authors: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Office of Scientific Research, Norte University, Asunción, Paraguay.
authors: Alcides
authors: A
authors: Chaux
authors: Roula
authors: R
authors: Albadine
authors: Luciana
authors: L
authors: Schultz
authors: Jessica
authors: J
authors: Hicks
authors: Michael A
authors: MA
authors: Carducci
authors: Pedram
authors: P
authors: Argani
authors: Mohamad
authors: M
authors: Allaf
authors: George J
authors: GJ
authors: Netto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008396:Maryland / Q000453:epidemiology; D008875:Middle Aged; D009392:Nephrectomy; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: 4EBP1; AKT; Chromophobe renal cell carcinoma; HIF-1α; PTEN; S6; mTOR