Proapoptotic Bad and Bid protein expression predict survival in stages II and III colon cancers.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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).

CONCLUSION:

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.

• Authors: Frank A Sinicrope, Rafaela L Rego, Nathan R Foster, Stephen N Thibodeau, Steven R Alberts, Harold E Windschitl, Daniel J Sargent
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 13 Pg. 4128-33 (Jul 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18593990 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BH3 Interacting Domain Death Agonist Protein
• bcl-Associated Death Protein

Topics

• Adult
• Aged
• Aged, 80 and over
• Apoptosis
• BH3 Interacting Domain Death Agonist Protein (biosynthesis)
• Colonic Neoplasms (metabolism)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Treatment Outcome
• bcl-Associated Death Protein (biosynthesis)