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.
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.
Garrity
Megan M
MM
Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. witzig@mayo.edu
Burgart
Lawrence J
LJ
Mahoney
Michelle R
MR
Windschitl
Harold E
HE
Salim
Muhammad
M
Wiesenfeld
Martin
M
Krook
James E
JE
Michalak
John C
JC
Goldberg
Richard M
RM
O'Connell
Michael J
MJ
Furth
Alfred F
AF
Sargent
Daniel J
DJ
Murphy
Linda M
LM
Hill
Eunice
E
Riehle
Darren L
DL
Meyers
Cecelia H
CH
Witzig
Thomas E
TE
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*
D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53