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

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.

Clinical genitourinary cancer. 2018 Jun 08 [Epub]

Osamu Ichiyanagi, Sei Naito, Hiromi Ito, Takanobu Kabasawa, Takafumi Narisawa, Hidenori Kanno, Yuta Kurota, Masayuki Kurokawa, Hiroki Fukuhara, Toshihiko Sakurai, Hayato Nishida, Tomoyuki Kato, Mitsunori Yamakawa, Norihiko Tsuchiya

Department of Urology, Yamagata University, Faculty of Medicine, Yamagata, Japan. Electronic address: ., Department of Urology, Yamagata University, Faculty of Medicine, Yamagata, Japan., Department of Pathological Diagnostics, Yamagata University, Faculty of Medicine, Yamagata, Japan., Department of Urology, Nihonkai General Hospital, Sakata, Japan.