title: Analysis of the p53/BAX pathway in colorectal cancer: low BAX is a negative prognostic factor in patients with resected liver metastases.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colarectal 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hematology, Oncology, and Tumor Immunology, Charité, Humboldt University, Berlin-Buch, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Sturm
authors.forename: C H
authors.initials: CH
authors.lastname: Köhne
authors.forename: G
authors.initials: G
authors.lastname: Wolff
authors.forename: H
authors.initials: H
authors.lastname: Petrowsky
authors.forename: T
authors.initials: T
authors.lastname: Hillebrand
authors.forename: S
authors.initials: S
authors.lastname: Hauptmann
authors.forename: M
authors.initials: M
authors.lastname: Lorenz
authors.forename: B
authors.initials: B
authors.lastname: Dörken
authors.forename: P T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D016368:Frameshift Mutation / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012189:Retrospective Studies; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein