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Raf Kinase Inhibitor Protein Expression in a Survival Analysis of Colorectal Cancer Patients

Fahd Al-Mulla, Suzanne Hagan, Abdulla I. Behbehani, Milad S. Bitar, Shirley S. George, James J. Going, Jorge J. Curto García, Lucy Scott, Nicky Fyfe, Graeme I. Murray, Walter Kolch

From the Kuwait University, Faculty of Medicine, Safat, Kuwait; Proteomics and Signalling Networks Group, Beatson Institute for Cancer Research; Department of Pathology, University of Glasgow; Centre for Oncology and Applied Pharmacology, Cancer Research UK, Beatson Laboratories, Glasgow; and the Department of Pathology, University of Aberdeen, Aberdeen, United Kingdom

Address reprint requests to Walter Kolch, MD, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Rd, Glasgow G61 1BD, United Kingdom; e-mail: wkolch{at}beatson.gla.ac.uk; and Fahd Al-Mulla, MB, ChB, PhD, Department of Pathology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait; email: fahd{at}al-mulla.org

PURPOSE: Raf kinase inhibitor protein (RKIP) inhibits the Raf and nuclear factor kappa B signaling pathways, and suppresses metastasis in animal models. We examined whether RKIP expression in primary colorectal cancers (CRCs) correlates with the risk of metastasis and overall survival.

PATIENTS AND METHODS: RKIP expression was examined immunohistochemically in three separate cohorts: a tissue microarray containing 276 samples from human tumors and normal tissues, and retrospective studies of 268 CRC patients and 65 early-stage CRCs. Overall and metastasis-free survival rates were measured.

RESULTS: RKIP was expressed in normal epithelia but was reduced in metastatic tumors. RKIP expression in primary CRC was an independent prognostic marker for survival using multivariate Cox regression analysis (hazard ratio, 2.808; 95% CI, 1.58 to 4.96; P = .0002), independent of Dukes' stage. Patients with Dukes' C RKIP-positive tumors had similar 5-year survival rates as early-stage patients if tumors had equivalent RKIP expression levels. An independent study of early-stage CRCs confirmed that reduced RKIP expression predicted metastatic recurrence and reduced disease-free survival (hazard ratio, 4.5; 95% CI, 1.7 to 12.3; P = .003). RKIP expression was independent of sex, age, mitotic index, lymphatic and vascular invasion, depth of invasion, and tumor site, but correlated positively with apoptotic index (P = .024). Weak or loss of RKIP expression was the most significant and independent prognostic marker using a multivariate regression equation (hazard ratio, 4.5; 95% CI, 1.7 to 12.3; P = .003).

CONCLUSION: RKIP expression in primary CRCs correlates with overall and disease-free survival, and can be useful for identifying early-stage CRC patients at risk of relapse.

Supported by Grant No. 99-07-07 from Kuwait Foundation for the Advancement of Sciences, Shared Facility Grant No. GM/0101 from Kuwait University, the Association for International Cancer Research (Grant No. 02-141), the European Union (FP6 STREP: COSBICS), the Chief Scientist Office of the Scottish Executive Health Department, and Cancer Research UK. The funding organizations did not have any role in the design or conduct of the study; collection, analysis, and interpretation of the data; and preparation and review of the manuscript.

Authors contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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