This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sturm, I. Articles by Daniel, P. T. Search for Related Content PubMed PubMed Citation Articles by Sturm, I. Articles by Daniel, P. T. Social Bookmarking                            What's this?

Analysis of the p53/BAX Pathway in Colorectal Cancer: Low BAX Is a Negative Prognostic Factor in Patients With Resected Liver Metastases

From the Department of Hematology, Oncology, and Tumor Immunology, Charité-Campus Berlin-Buch, Humboldt University; Max Delbrück Center for Molecular Medicine; InViTek GmbH, Berlin-Buch; Institute of Pathology, Charité-Campus Berlin-Mitte, Berlin; and Department of General and Vascular Surgery, University Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany.

Address reprint requests to Peter Daniel, MD, Department of Hematology, Oncology, and Tumor Immunology, Charité-Campus Berlin-Buch, Humboldt-University, Lindenberger Weg 80, 13125 Berlin-Buch, Germany; email pdaniel{at}mdc-berlin.de

PURPOSE: To determine the prognostic value of the central downstream apoptosis effector BAX in relation to its upstream regulator p53 in R0-resected hepatic metastases of colorectal cancer.

PATIENTS AND METHODS: Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colorectal cancer was performed. Tumor DNA was screened for p53 mutations by single-stranded conformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. Protein expression of BAX, p21, and p53 was investigated by immunohistochemistry.

RESULTS: Overall median survival was 40.2 months. Tumors with BAX frameshift mutations were considered microsatellite mutator phenotype–positive and were excluded from further prognostic analyses. Patients with high BAX protein expression had a median survival of 53.6 months compared with 35.4 months for patients with low BAX expression (P < .05). The negative prognostic value of low BAX expression was more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P < .01). Low BAX expression was an independent negative prognostic marker in multivariate regression analysis for all patients independent of the p53 status (relative risk, 3.03, P = .03), especially for p53 wild-type tumors (relative risk, 8.21; P = .0095).

CONCLUSION: We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer. The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its downstream death effector, BAX) might yield more prognostic power in future studies as compared with analysis of single genes such as p53 alone.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				P. Grabowski, J. Schrader, J. Wagner, D. Horsch, R. Arnold, C. N. Arnold, I. Georgieva, H. Stein, M. Zeitz, P. T. Daniel, et al. Loss of Nuclear p27 Expression and Its Prognostic Role in Relation to Cyclin E and p53 Mutation in Gastroenteropancreatic Neuroendocrine Tumors Clin. Cancer Res., November 15, 2008; 14(22): 7378 - 7384. [Abstract] [Full Text] [PDF]

				I Zlobec and A Lugli Prognostic and predictive factors in colorectal cancer Postgrad. Med. J., August 1, 2008; 84(994): 403 - 411. [Abstract] [Full Text] [PDF]

				I Zlobec and A Lugli Prognostic and predictive factors in colorectal cancer J. Clin. Pathol., May 1, 2008; 61(5): 561 - 569. [Abstract] [Full Text] [PDF]

				D. G. Mollevi, T. Serrano, M. M. Ginesta, J. Valls, J. Torras, M. Navarro, E. Ramos, J. R. Germa, E. Jaurrieta, V. Moreno, et al. Mutations in TP53 are a prognostic factor in colorectal hepatic metastases undergoing surgical resection Carcinogenesis, June 1, 2007; 28(6): 1241 - 1246. [Abstract] [Full Text] [PDF]

				T. Stuhmer, M. Chatterjee, M. Hildebrandt, P. Herrmann, H. Gollasch, C. Gerecke, S. Theurich, L. Cigliano, R. A. Manz, P. T. Daniel, et al. Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma Blood, November 15, 2005; 106(10): 3609 - 3617. [Abstract] [Full Text] [PDF]

				R. L. Hayward, J. S. Macpherson, J. Cummings, B. P. Monia, J. F. Smyth, and D. I. Jodrell Enhanced oxaliplatin-induced apoptosis following antisense Bcl-xl down-regulation is p53 and Bax dependent: Genetic evidence for specificity of the antisense effect Mol. Cancer Ther., February 1, 2004; 3(2): 169 - 178. [Abstract] [Full Text] [PDF]

				C. Gessner, C. Woischwill, A. Schumacher, U. Liebers, H. Kuhn, P. Stiehl, K. Jurchott, H.D. Royer, C. Witt, and G. Wolff Nuclear YB-1 expression as a negative prognostic marker in nonsmall cell lung cancer Eur. Respir. J., January 1, 2004; 23(1): 14 - 19. [Abstract] [Full Text] [PDF]

				B. Rau, I. Sturm, H. Lage, S. Berger, U. Schneider, S. Hauptmann, P. Wust, H. Riess, P. M. Schlag, B. Dorken, et al. Dynamic Expression Profile of p21WAF1/CIP1 and Ki-67 Predicts Survival in Rectal Carcinoma Treated With Preoperative Radiochemotherapy J. Clin. Oncol., September 15, 2003; 21(18): 3391 - 3401. [Abstract] [Full Text] [PDF]

				R. L. Hayward, J. S. Macpherson, J. Cummings, B. P. Monia, J. F. Smyth, and D. I. Jodrell Antisense Bcl-xl Down-Regulation Switches the Response to Topoisomerase I Inhibition from Senescence to Apoptosis in Colorectal Cancer Cells, Enhancing Global Cytotoxicity Clin. Cancer Res., July 1, 2003; 9(7): 2856 - 2865. [Abstract] [Full Text] [PDF]

				A. Jansson and X.-F. Sun Bax Expression Decreases Significantly From Primary Tumor to Metastasis in Colorectal Cancer J. Clin. Oncol., February 1, 2002; 20(3): 811 - 816. [Abstract] [Full Text] [PDF]

				C. Gessner, U. Liebers, H. Kuhn, P. Stiehl, C. Witt, J. Schauer, and G. Wolff BAX and p16INK4A are independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer Eur. Respir. J., January 1, 2002; 19(1): 134 - 140. [Abstract] [Full Text] [PDF]

				I. Sturm, H. Petrowsky, R. Volz, M. Lorenz, S. Radetzki, T. Hillebrand, G. Wolff, S. Hauptmann, B. Dorken, and P. T. Daniel Analysis of p53/BAX/p16ink4a/CDKN2 in Esophageal Squamous Cell Carcinoma: High BAX and p16ink4a/CDKN2 Identifies Patients With Good Prognosis J. Clin. Oncol., April 15, 2001; 19(8): 2272 - 2281. [Abstract] [Full Text] [PDF]

				P. T. Daniel, K.-T. Pun, S. Ritschel, I. Sturm, J. Holler, B. Dorken, and R. Brown Expression of the Death Gene Bik/Nbk Promotes Sensitivity to Drug-Induced Apoptosis in Corticosteroid-Resistant T-Cell Lymphoma and Prevents Tumor Growth in Severe Combined Immunodeficient Mice Blood, August 1, 1999; 94(3): 1100 - 1107. [Abstract] [Full Text] [PDF]

				E. C. Thornborrow and J. J. Manfredi The Tumor Suppressor Protein p53 Requires a Cofactor to Activate Transcriptionally the Human BAX Promoter J. Biol. Chem., May 4, 2001; 276(19): 15598 - 15608. [Abstract] [Full Text] [PDF]