Raf Kinase inhibitor protein expression in a survival analysis of colorectal cancer patients

F. Al-Mulla, S. Hagan, A. I. Behbehani, M. S. Bitar, S. S. George, J. J. Going, J. J. Curto Garcia, L. Scott, N. Fyfe, Graeme Ian Murray, W. Kolch

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Abstract

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.

Original languageEnglish
Pages (from-to)5672-5679
Number of pages7
JournalJournal of Clinical Oncology
Volume24
DOIs
Publication statusPublished - 2006

Keywords

  • COLON-CANCER
  • DUKES-B
  • TISSUE MICROARRAY
  • PROSTATE-CANCER
  • MAP KINASE
  • METASTASIS
  • PROGNOSIS
  • RKIP
  • SUPPRESSION
  • MARKERS

Cite this

Al-Mulla, F., Hagan, S., Behbehani, A. I., Bitar, M. S., George, S. S., Going, J. J., Curto Garcia, J. J., Scott, L., Fyfe, N., Murray, G. I., & Kolch, W. (2006). Raf Kinase inhibitor protein expression in a survival analysis of colorectal cancer patients. Journal of Clinical Oncology, 24, 5672-5679. https://doi.org/10.1200/JCO.2006.07.5499