Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers.
OBJECTIVE
Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival.


METHODS
Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates.


RESULTS
High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004).


CONCLUSIONS
Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.
Sinicrope
Frank A
FA
Division of Oncology, Mayo Clinic, Guggenheim 10-11C, 200 1st Street Southwest, Rochester, MN 55905, USA. sinicrope.frank@mayo.edu
Rego
Rafaela L
RL
Foster
Nathan R
NR
Thibodeau
Stephen N
SN
Alberts
Steven R
SR
Windschitl
Harold E
HE
Sargent
Daniel J
DJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis*; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D051025:bcl-Associated Death Protein / Q000096:biosynthesis*
D051023:BH3 Interacting Domain Death Agonist Protein; D051025:bcl-Associated Death Protein