Phospho-4e-BP1 and eIF4E overexpression synergistically drives disease progression in clinically confined clear cell renal cell carcinoma

Campbell, Lee, Jasani, Bharat, Griffiths, David F. R. and Gumbleton, Mark ORCID: https://orcid.org/0000-0002-7386-311X 2015. Phospho-4e-BP1 and eIF4E overexpression synergistically drives disease progression in clinically confined clear cell renal cell carcinoma. American Journal of Cancer Research 5 (9) , pp. 2838-2848.

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Abstract

Clear cell renal cell carcinoma (ccRCC), the most aggressive and lethal form of renal cell carcinoma accounts for over 90% of metastasis that occur following curative surgery for clinically confined disease. High relapse rates have prompted the evaluation of targeted therapies for the prevention or delay of metastatic disease in high-risk patients, with biomarkers offering significant potential to guide and improve patient management in this setting. In this current study we examined the value of the 4E-BP1/eIF4E axis for prognostic significance and risk stratification in patients with clinically confined ccRCC. This axis is a critical convergence point for many signalling pathways that are targeted by current therapies for the treatment of advanced RCC. Immunohistochemistry for phosphorylated 4E-BP1 (p4E-BP1) and total eIF4E was performed on tissue microarrays containing tumour cores from 135 patients with localised ccRCC. For both biomarkers 39% of all evaluable cores stained positive, with a strong correlation observed between the presence of p4E-BP1 and the overexpression of eIF4E within the same tumour (P = 0.005). Further, the combined expression of p4E-BP1 and eIF4E was associated with significantly worse disease-free survival of 2.9 vs 5.7 yrs compared to patients whose tumours expressed only one, or neither, of the biomarkers (P < 0.001). Cox-regression analysis confirmed the ability of the p4EBP1/eIF4E signature to independently identify high-risk patients with a Hazard Ratio of 4.2 (CI = 2.1-8.6; P < 0.001), compared to 3.3 for tumour grade 3 and 4, and 2.3 for tumour stage 3 and 4. These data show the powerful prognostic value of the p4E-BP1/eIF4E signature for potential management of patients with clinically confined ccRCC, and in addition provides insights into the possible key synergistic determinants of disease progression and treatment response.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	Clear cell renal cell carcinoma, ccRCC, metastatic disease, 4E-BP1, eIF4E, biomarker, prognosis, stratification, immunohistochemistry, mTOR
Additional Information:	This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license
Publisher:	e-Century Publishing
ISSN:	2156-6976
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	4 August 2015
Last Modified:	17 Nov 2024 02:00
URI:	https://orca.cardiff.ac.uk/id/eprint/77362

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