Expression of molecular markers associated with the mammalian target of rapamycin pathway in nonmetastatic renal cell carcinoma: Effect on prognostic outcomes following radical nephrectomy.
OBJECTIVE
To evaluate the expression of multiple molecular markers involved in mammalian target of rapamycin (mTOR) signaling pathway in renal cell carcinoma (RCC) to determine the prognostic significance of these markers following radical nephrectomy.


METHODS
The expression levels of 5 markers, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, and p-4E-binding protein 1 (4E-BP1), were measured in radical nephrectomy specimens from 137 patients with nonmetastatic RCC by immunohistochemical staining.


RESULTS
During the follow-up period of this series (median, 63.5 mo), disease recurrence occurred in 59 of the 137 patients (43.0%), with a 5-year recurrence-free survival rate of 58.3%. On Univariate analysis, expression levels of p-mTOR and p-4E-BP1, in addition to the C-reactive protein level, pathological stage, and microvascular invasion, were identified as significant predictors for disease recurrence. Of these factors, the expression of p-4E-BP1, C-reactive protein level, and pathological T stage appeared to be independently related to recurrence-free survival on multivariate analysis. Moreover, significant differences were observed in recurrence-free survival according to the positive numbers of these 3 independent factors; that is, disease recurrence developed in 5 of 42 patients with negative results for any risk factor (11.9%), 23 of 50 patients with positive results for a single risk factor (46.0%), and 31 of 45 patients with positive results for 2 or 3 risk factors (68.8%).


CONCLUSIONS
The combined evaluation of the expression levels of potential markers in the mTOR signaling pathway, particularly p-4E-BP1, in RCC specimens with conventional prognostic parameters would contribute to the accurate prediction of disease recurrence following radical nephrectomy for nonmetastatic RCC.
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
Masatomo
M
Nishikawa
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. Electronic address: hideakimiyake@hotmail.com.
Hideaki
H
Miyake
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
Ken-ichi
K
Harada
Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.
Masato
M
Fujisawa
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002097:C-Reactive Protein / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009392:Nephrectomy / Q000379:methods; D017063:Outcome Assessment, Health Care; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D010750:Phosphoproteins / Q000096:biosynthesis; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000096:biosynthesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis*
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D002097:C-Reactive Protein; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
4E-BP1; Prognosis; Radical nephrectomy; Renal cell carcinoma; mTOR pathway