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Expression of 4EBP1 is an influential prognostic covariate in renal cell carcinoma [Abstract]

Campbell, Lee, Jasani, Bharat, Gumbleton, Mark, Edwards, K. and Griffiths, D. F. 2008. Expression of 4EBP1 is an influential prognostic covariate in renal cell carcinoma [Abstract]. Modern Pathology 21 (1s) , 150A. 10.1038/sj.modpathol.3801035

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Background: The outcome of surgically treated localized renal cell carcinoma is unpredictable, up to 40% of patients apparently cured by surgery go on to develop metastasis and die from these. There is a need for better prognostic markers to determine the need for adjuvant therapy. Dysregulation of the MTOR pathway is recognized in renal cell carcinoma and some novel therapies inhibit this pathway; but to date there are no reports of the impact of the expression of phosphorolated 4E binding protein 1 (4EBP1), an important effector component of this pathway, on prognosis. Design: A cohort of 174 clinically localized RCCs treated by radical nephrectomy and for whom good follow up was available were studied. Data derived from the original report and a chart review included tumor size, time to first recurrence and date and cause of death. Slides and blocks were retrieved and the tumors assessed for tumor type, nuclear grade, vascular invasion (VI) (IVC, renal vein or microvascular invasion) and invasion of perinephric tissue. A tissue microarray was constructed and stained by convention immunohistochemical technique for 4EPB1. Staining for these antigen was assessed blinded to the outcome and scored on a semiquantitative scale. This was converted into a binary value by thresholding according to the most informative cut off value on Kaplan Meier analysis. Impact on disease free survival (DFS) was assessed by Kaplan Meier method and Cox regression analysis. Results: After thresholding 65 cases scored positively for 4EBP1. On Kaplan Meier analysis positive 4EBP1 had a adverse impact on DFS p=0.033 (Breslow test). On Cox regression analysis including grade, vascular invasion and invasion of perinephric tissue E4BP1 was found to have significant additional influence on the outcome: positive 4EBP1 vrs negative 4EBP1 HR: 3.2 (p<0.001). Conclusions: This is the first report of the impact of the expression of 4EBP1 on disease free survival in localised RCC. and demonstrates it has powerful influence on survival in both univariate and multivariate analysis. This implies the pathway is important in the pathogenesis of the aggressiveness of the RCC and offers a novel prognostic marker. We postulate that expression of 4EBP1 may also be predictive in the response of tumors to inhibitors of the MTOR pathway.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 0893-3952
Last Modified: 05 Nov 2019 03:39

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