title: Thymidylate synthase expression and p21(WAF1)/p53 phenotype of colon cancers identify patients who may benefit from 5-fluorouracil based therapy.
abstract: BACKGROUND
  Studies on the expression of thymidylate synthase (TS) in colorectal cancers (CRCs) have failed to provide unequivocal prognostic or predictive information. Here, we assessed the prognostic significance of TS expression in Astler-Coller stage B2 and C CRCs defined by a p21(WAF1)/p53 immunophenotype in patients subjected to 5-fluorouracil (5FU)-based adjuvant therapy.
  
  
  METHODS
  A cohort of 189 CRCs was asssessed for TS, p21(WAF1) and p53 expression on tissue microarrays using immunohistochemistry, and associations with disease-free survival (DFS) and overall survival (OS) of the patients were assessed using univariate and multivariate analyses.
  
  
  RESULTS
  TS expression led to the stratification of patients with colon cancer, but not rectal cancer, with immunophenotypes other than p21(WAF1)+/p53- (referred to as P&P) into subgroups characterized by a worse (P&P TS+) and a better (P&P TS-) DFS and OS, in univariate (P = 0.006 and P = 0.005, respectively) and multivariate (P = 0.0004 and P = 0.002, respectively) analyses. The p21(WAF1)+/p53- immunophenotype was associated with a favorable prognosis, irrespective of TS expression.
  
  
  CONCLUSIONS
  The strong association observed between the P&P TS+ immunophenotype and a worse DFS and OS suggests a predictive significance of TS expression for 5FU-based adjuvant therapy in patients with colon cancers exhibiting the P&P immunophenotype. In addition, our findings suggest that the appropriate target for assessment of TS expression as a prognostic/predictive marker is a subgroup of colon cancers with an immunophenotype other than p21(WAF1)+/p53-, and that only in this subgroup high TS expression is associated with an unfavorable DFS and OS. Therefore, we suggest that assessing TS expression in conjunction with p21(WAF1)/p53 immunophenotyping of colon cancers may improve the selection of patients suitable for 5FU-based adjuvant chemotherapy.
authors.affiliation: Department of Clinical Oncology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Violetta
authors.initials: V
authors.lastname: Sulzyc-Bielicka
authors.forename: Pawel
authors.initials: P
authors.lastname: Domagala
authors.forename: Dariusz
authors.initials: D
authors.lastname: Bielicki
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Safranow
authors.forename: Wenancjusz
authors.initials: W
authors.lastname: Domagala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D059248:Chemoradiotherapy; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000601:surgery / Q000628:therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000378:metabolism*; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; D005472:Fluorouracil