Prognostic Significance of TRAIL Signaling Molecules in Stage II and III Colorectal Cancer

Donal P. McLornan, Helen L. Barrett, Robert Cummins, Ultan McDermott, Cliona McDowell, Susie J. Conlon, Victoria M. Coyle, Sandra Van Schaeybroeck, Richard Wilson, Elaine W. Kay, Daniel B. Longley, Patrick G. Johnston

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Abstract

Purpose: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.

Experimental Design: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil–based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry.

Results: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001).

Conclusions: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse.
Original languageEnglish
Pages (from-to)3442-3451
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number13
DOIs
Publication statusPublished - 01 Jul 2010

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    McLornan, D. P., Barrett, H. L., Cummins, R., McDermott, U., McDowell, C., Conlon, S. J., Coyle, V. M., Van Schaeybroeck, S., Wilson, R., Kay, E. W., Longley, D. B., & Johnston, P. G. (2010). Prognostic Significance of TRAIL Signaling Molecules in Stage II and III Colorectal Cancer. Clinical Cancer Research, 16(13), 3442-3451. https://doi.org/10.1158/1078-0432.CCR-10-0052