title: Clinical implications of p53 tumor suppressor gene mutation and protein expression in esophageal adenocarcinomas: results of a ten-year prospective study.
abstract: OBJECTIVE
  This study was undertaken to characterize the spectrum of p53 alterations (mutations and protein expression) in surgically resected esophageal adenocarcinomas, and to correlate molecular alterations with clinicopathologic findings and outcome.
  
  
  METHODS
  Between 1991 and 2001, 91 consecutive patients with esophageal adenocarcinomas underwent subtotal esophagectomy. No patient received induction therapy. Strict clinicopathologic criteria were used to define primary esophageal adenocarcinomas. Genomic DNA was extracted from esophageal tumors, each matched with histologically normal esophageal epithelium (internal control) from the resection margin. Polymerase chain reaction was used to amplify p53 exons 4 through 10. Mutations were studied by single-strand conformation polymorphism analysis and direct DNA sequencing. Immunohistochemical testing (monoclonal antibody DO7) was used to evaluate p53 protein distribution.
  
  
  RESULTS
  Five-year overall survival was 27.3%. No p53 alterations (mutations and/or protein overexpression) were found in normal esophageal epithelium. A total of 57.1% (n = 52) of tumors had p53 alterations (mutations and/or protein overexpression), which on univariate analysis were associated with poor tumor differentiation (P =.001), advanced pTNM stage (P =.009), and number of involved lymph nodes (0, 1-3, >3; P =.04). Patients with p53 alterations had significantly reduced 5-year overall survival relative to patients with wild-type p53 (15% vs 46%; P =.004). The p53 mutations were predominantly G:C to A:T transitions at CpG dinucleotides (52.2%, 24/46)
  
  
  CONCLUSIONS
  We conclude that p53 alterations (mutations and/or protein overexpression) are a predictor of reduced postoperative survival after surgical resection of esophageal adenocarcinomas and that p53 may be a clinically useful molecular marker for stratifying patients in future clinical trials. Patterns of p53 mutations suggest endogenous mutational mechanisms.
authors.affiliation: Departments of Surgery, Pathology, and Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada. alan.casson@dalca
authors.forename: Alan G
authors.initials: AG
authors.lastname: Casson
authors.forename: Susan C
authors.initials: SC
authors.lastname: Evans
authors.forename: Amy
authors.initials: A
authors.lastname: Gillis
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Porter
authors.forename: Paul
authors.initials: P
authors.lastname: Veugelers
authors.forename: S Jane
authors.initials: SJ
authors.lastname: Darnton
authors.forename: Duane L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016629:Esophagectomy / Q000379:methods; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D017052:Hospital Mortality; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D011446:Prospective Studies; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53