title: 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.
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 (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.
  
  
  RESULTS
  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).
  
  
  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.
authors.affiliation: Second Department of Pathology, University of Athens, Attikon University Hospital, Athens, Greece.
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Anna
authors.initials: A
authors.lastname: Koumarianou
authors.forename: Efstratios S
authors.initials: ES
authors.lastname: Patsouris
authors.forename: George
authors.initials: G
authors.lastname: Peros
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis / Q000175:diagnosis* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16