Clinical implications of p53 tumor suppressor gene alterations in esophageal adenocarcinoma: results of a 10-year prospective study

AG Casson, FRCSC, a S Evans, BSc, a A Gillis, BSc, a GA Porter, MD, a PJ Veugelers, PhD, a SJ Darnton, PhD, a DL Guernsey, PhD, a P Hainaut, PhD b

a Dalhousie University, Halifax, Nova Scotia Canada, b International Agency for Research on Cancer, Lyon, France

AIM: To characterize the spectrum of p53 alterations (mutations and protein expression) in surgically resected esophageal adenocarcinoma (EADC), and to correlate molecular alterations with clinico-pathologic findings and outcome. METHODS: Between 1991 and 2001, 91 consecutive patients with EADC underwent subtotal esophagectomy. No patient received induction therapy. Strict clinico-pathologic criteria were used to define primary EADC. Genomic DNA was extracted from esophageal tumors, each with matched histologically normal esophageal epithelium (internal control) from the resection margin. Polymerase chain reaction was used to amplify p53 exons 4-10. Mutations were studied by single-strand conformation polymorphism analysis and direct DNA sequencing. Immunohistochemistry (monoclonal antibody DO7) was used to evaluate p53 protein distribution. RESULTS: For all patients, 5-year overall survival (OS) was 25%, with median follow-up of 32 months. No p53 alterations were found in normal esophageal epithelium. 57% (n=52) of tumors had p53 alterations (missense mutations with protein overexpression, n=28; truncating mutations, n=19; protein overexpression only, n=5), and were associated with poor tumor differentiation (p=0.001), advanced (pTNM) stage (p=0.009), and number of involved lymph nodes (0, 1-3, >3; p=0.04). Patients with p53 positive tumors (mutations and/or protein) had significantly reduced 5-year OS compared with patients with p53 negative tumors (15% vs. 46%; p=0.004). CONCLUSIONS: We conclude that 1) p53 alterations (mutations and/or protein expression) are a significant predictor of reduced postoperative survival following surgical resection of EADC, and 2) p53 may be a clinically useful molecular marker for stratifying patients in future clinical trials.

KEY WORDS: esophagus, adenocarcinoma, p53.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.