Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas

• Published in: Clinical cancer research 2008-09, Vol.14 (18), p.5810-5818
• Main Authors: SINICROPE, Frank A, REGO, Rafaela L, OKUMURA, Kenji, FOSTER, Nathan R, O'CONNELL, Michael J, SARGENT, Daniel J, WINDSCHITL, Harold E
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; BH3 Interacting Domain Death Agonist Protein - metabolism; Bim; Biological and medical sciences; Biomarkers, Tumor - analysis; colon cancer; Colonic Neoplasms - diagnosis; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Fluorouracil - therapeutic use; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Medical sciences; Membrane Proteins - metabolism; Noxa; Pharmacology. Drug treatments; Prognosis; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Puma; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-5202

Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates. Experimental Design: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil–based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays ( n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates. Results: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS ( P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS ( P = 0.0034) and OS ( P = 0.0011). Conclusions: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil–based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.