Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups

Abstract

BACKGROUND: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. METHODS: 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 (b-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, laminin5c2, mucin 1 [MUC1], and caudal-related homeobox 2). The prognostic effects of biomarkers in both primary tumor and positive LNs were assessed. RESULTS: MUC1, pERK and p16 in LN (P ¼ .002, P ¼ .014, and P ¼ .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 ¼ .005) when the analysis was stratified by pathologic tumor classification (HR, 0.25; 95% CI, 0.1-0.7; P ¼ .005), age (HR, 0.23; 95% CI, 0.1-0.6; P ¼ .004), and LN ratio (HR, 0.26; 95% CI, 0.1-0.7; P ¼ .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 ¼ .03). CONCLUSIONS: 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;116:4474-86.

Alterations in the tumor suppressor gene p16 INK4A are associated with aggressive behavior of penile carcinomas

“…Inactivation of the tumor suppressor p16 INK4A seems to play an important role in tumor progression and dissemination [34]. In accordance to squamous cell carcinomas of other origins, we were able to demonstrate a more aggressive behavior of p16-negative tumors.…”

Keratin 7 expression in lymph node metastases but not in the primary tumour correlates with distant metastases and poor prognosis in colon carcinoma

“…Expression of many markers in LNM, including thymidylate synthase [24], epidermal growth factor receptor (EGFR) [25] and p16 [26], shows better Similar observations were found in other cancers, for example in breast carcinoma [8].…”

MicroRNA-372 Is Associated with Poor Prognosis in Colorectal Cancer

“…Previous studies showed that cell cycle progression led to poor prognosis or liver metastasis due to inactivation of p16 INK4a or p27 KIP1 or to activation of cyclin D2 at the G1/S transition [28,29,30], or due to overexpression of CDC25B acting at the G2/M checkpoint [31]. Like other cell cycle regulatory components, it is likely that decreases in LATS2 expression lead to similar unfavorable outcomes in patients with CRC.…”