title: Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas.
abstract: Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non-clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
authors.forename: Alcides
authors.initials: A
authors.lastname: Chaux
authors.forename: Luciana
authors.initials: L
authors.lastname: Schultz
authors.forename: Roula
authors.initials: R
authors.lastname: Albadine
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Kim
authors.forename: Mohamad E
authors.initials: ME
authors.lastname: Allaf
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Ronald
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Hammers
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018797:Cell Cycle Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D010766:Phosphorylation; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases