Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas

Abstract

Summary 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.

Distinctive expression patterns of glycoprotein non‐metastatic B and folliculin in renal tumors in patients with Birt–Hogg–Dubé syndrome

“…However, mTOR pathway molecules are also overexpressed in sporadic RCCs. (19,20) These ubiquitously upregulated molecules cannot be used for differential diagnosis.…”

“…We confirmed overexpression of phospho‐S6, a downstream molecule of mTOR complex 1, in FLCN ‐related RCCs (data not shown). However, mTOR pathway molecules are also overexpressed in sporadic RCCs . These ubiquitously upregulated molecules cannot be used for differential diagnosis.…”

Phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat in advanced renal cell carcinoma and other solid tumors

“…[28] In their study the investigators examined a variety of biomarkers from the nephrectomy specimens of 54 patients with papillary RCC. They noted significant increases in the expression of 4E-BP1 (which is activated by mTOR) and HIF-1α in the tumor samples as compared to normal kidney tissue specimens.…”

Clinical Applications of Recent Molecular Advances in Urologic Malignancies

“…In addition, the sequential use (as opposed to integration into a new model) of BioScore with existing clinicopathologic scoring systems (TNM, UISS, and SSIGN) further enhanced the predictive ability compared with each of these scoring systems alone. 297,298 Using a similar tissue microarray and immunohistochemistry analysis approach, we recently were also able to demonstrate evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary RCC. A promising prognostic role for mTOR pathway members was initially pointed out by Pantuck et al 295,296 Their study revealed an independent negative prognostic role for PTEN loss and pS6k overexpression.…”

“…Prospective validation of these biomarker prognostic models is required before routine clinical use can come about. 297,298 A prognostic role for angiogenesis pathway is illustrated in RCC. The same study showed increased pAKT cytoplasmic expression and loss of pAKT nuclear expression to be negative predictors of survival.…”