Levels of 4EBP1/eIF4E Activation in Renal Cell Carcinoma Could Differentially Predict Its Early and Late Recurrence

A subset of patients who undergo curative surgery for localized clear cell renal cell carcinoma (ccRCC) will experience early or late recurrence. Tumor viability depends on protein synthesis via the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1/eIF4E) axis. Activation levels of the axis in ccRCC tissues could differentially affect tumor recurrence and the timing of recurrence after curative nephrectomy. The objective was to explore the predictive markers of late recurrence (LR) > 5 years after curative nephrectomy for renal cell carcinoma (RCC). We retrospectively examined the data from 303 patients with localized clear cell RCC treated surgically at our institution from 1993 to 2011. Activation of the eukaryotic initiation factor (eIF)4E-binding protein 1 (4EBP1)/eIF4E axis at the mammalian target of rapamycin complex 1 (mTORC1) was evaluated in the tumor specimens. Weak, intermediate, and strong immunohistochemistry staining grades were defined for 4EBP1, phosphorylated 4EBP1, and eIF4E. The effects of clinicopathologic factors and activation level grades on tumor recurrence were analyzed using multivariate Cox regression models. To validate the present findings, we investigated clinical data from The Cancer Genome Atlas and protein/phosphoprotein data from corresponding patients from The Cancer Proteome Atlas. Of the 303 patients, 31 and 16 patients developed early recurrence (ER, ≤ 5 years) and LR, respectively. The activation levels were comparable among the subcategories of pathologic TN stage, Fuhrman grade, and microvascular and capsular invasion. Pathologic stage ≥ T1b, Fuhrman grade 3/4, and an intermediate or strong activation level correlated significantly with overall recurrence and ER. Strong activation of the axis and pathologic stage ≥ T1b were identified as independent predictors of LR. Only 2 patients with weak activation experienced recurrence (1 each with ER and LR). Similar results were confirmed by the analyses of The Cancer Genome Atlas and The Cancer Proteome Atlas data. The activation level of the axis in RCC tissues could independently predict for recurrence and differentially affect the timing of recurrence.