title: Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study.
abstract: OBJECTIVE
  Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas.
  
  
  METHODS
  Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS).
  
  
  RESULTS
  Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P <.05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P <.01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant.
  
  
  CONCLUSIONS
  This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.
authors.affiliation: Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. witzig@mayo.edu
authors.forename: Megan M
authors.initials: MM
authors.lastname: Garrity
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Burgart
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Harold E
authors.initials: HE
authors.lastname: Windschitl
authors.forename: Muhammad
authors.initials: M
authors.lastname: Salim
authors.forename: Martin
authors.initials: M
authors.lastname: Wiesenfeld
authors.forename: James E
authors.initials: JE
authors.lastname: Krook
authors.forename: John C
authors.initials: JC
authors.lastname: Michalak
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connell
authors.forename: Alfred F
authors.initials: AF
authors.lastname: Furth
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Linda M
authors.initials: LM
authors.lastname: Murphy
authors.forename: Eunice
authors.initials: E
authors.lastname: Hill
authors.forename: Darren L
authors.initials: DL
authors.lastname: Riehle
authors.forename: Cecelia H
authors.initials: CH
authors.lastname: Meyers
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D020137:Base Pair Mismatch; D014408:Biomarkers, Tumor / Q000032:analysis*; D002455:Cell Division; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D004260:DNA Repair; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D011003:Ploidies; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53