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J Thorac Cardiovasc Surg 2003;125:1121-1131
© 2003 The American Association for Thoracic Surgery

General Thoracic Surgery

Clinical implications of p53 tumor suppressor gene mutation and protein expression in esophageal adenocarcinomas: Results of a ten-year prospective study

From the Departments of Surgery,^a Pathology,^b and Community Health and Epidemiology,^c Dalhousie University, Halifax, Nova Scotia, Canada, and the Molecular Carcinogenesis Group, International Agency for Research on Cancer,^d Lyon, France.

Funded by The Dalhousie Medical Research Foundation, The Dalhousie University Department of Surgery, The Cancer Care Nova Scotia Surgical Oncology Network, and The QEII Health Science Centre Research Fund. Amy Gillis was supported by a Canadian Institutes for Health Research-Burrows Wellcome Fund/University of Toronto Faculty of Medicine Student Research Award (2001).

Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.

Received for publication May 14, 2002. Accepted for publication Aug 5, 2002. Address for reprints: Alan G. Casson, MD, Division of Thoracic Surgery, QEII Health Sciences Centre, Victoria Building 7S-013, 1278 Tower Rd, Halifax, Nova Scotia, B3H 2Y9, Canada (E-mail: alan.casson{at}dal.ca).

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.

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