The first two authors contributed equally to this article.
Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups
A retrospective analysis of biomarkers in matched primary tumor and lymph node metastases
Article first published online: 19 AUG 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 19, pages 4474–4486, 1 October 2010
How to Cite
Karamitopoulou, E., Zlobec, I., Koumarianou, A., Patsouris, E. S., Peros, G. and Lugli, A. (2010), Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups. Cancer, 116: 4474–4486. doi: 10.1002/cncr.25304
- Issue published online: 22 JUN 2010
- Article first published online: 19 AUG 2010
- Manuscript Accepted: 1 FEB 2010
- Manuscript Revised: 9 JAN 2010
- Manuscript Received: 22 OCT 2009
- colorectal cancer;
- lymph nodes;
- TNM classification;
- stage III
The objective of identifying protein biomarkers for patients with stage III and IV colorectal cancer is to improve risk stratification and, thus, to identify patients in the postoperative setting who may benefit from more targeted treatment. The objective of the current study was to determine the prognostic value of 19 protein markers assessed in primary tumors and matched lymph node (LN) metastases from patients with stage III and IV colorectal cancer.
Matched primary tumors and LN metastases from 82 patients with stage III and IV colorectal cancer were mounted onto a multiple-punch tissue microarray and were stained for 19 protein markers involved in tumor progression (β-catenin, E-cadherin, epidermal growth factor receptor, phosphorylated extracellular signal-regulated kinase [pERK], receptor for hyaluronic acid-mediated motility, phosphorylated protein kinase B, p21, p16, B-cell lymphoma 2, Ki67, apoptotic protease activating factor 1, mammalian sterile 20-like kinase 1, Raf kinase inhibitor protein, vascular endothelial growth factor, ephrin type-B receptor 2, matrix metalloproteinase 7, laminin5γ2, mucin 1 [MUC1], and caudal-related homeobox 2). The prognostic effects of biomarkers in both primary tumor and positive LNs were assessed.
MUC1, pERK and p16 in LN (P = .002, P = .014, and P = .002, respectively) had independent prognostic value. In patients with stage III disease who received adjuvant treatment, negative p16 expression was associated with highly unfavorable outcomes overall (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.1-0.6; P = .005) when the analysis was stratified by pathologic tumor classification (HR, 0.25; 95% CI, 0.1-0.7; P = .005), age (HR, 0.23; 95% CI, 0.1-0.6; P = .004), and LN ratio (HR, 0.26; 95% CI, 0.1-0.7; P = .007); and, in multivariate analysis, it was associated with performance status and the receipt of folic acid treatment (HR, 0.29; 95% CI, 0.09-0.89; P = .03).
The loss of p16 in LN metastases contributed to adverse outcomes in adjuvantly treated patients with stage III colorectal cancer independent of pathologic tumor classification, age, LN ratio, performance status, or folic acid treatment. The current results support the investigation of p16 as a prognostic and potential predictive biomarker for future randomized trials of patients with stage III colorectal cancer. Cancer 2010. © 2010 American Cancer Society.