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The Molecular Signature of Normal Squamous Esophageal Epithelium Identifies the Presence of a Field Effect and Can Discriminate between Patients with Barrett's Esophagus and Patients with Barrett's-Associated Adenocarcinoma

Departments of ¹ Visceral and Vascular Surgery, and ² Pathology, University of Cologne, Cologne, Germany; ³ Department of Preventive Medicine, University of Southern California; Departments of ⁴ Surgery and ⁵ Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine and USC/Kenneth Norris Comprehensive Cancer Center; ⁶ Response Genetics Inc., Los Angeles, California; and ⁷ GI Division, Department of Medicine, University of Maryland School of Medicine and VA Medical Center, and Greenebaum Cancer Center, Baltimore, Maryland

Requests for reprints: Jan Brabender, Department of Visceral and Vascular Surgery, University of Cologne, Joseph-Stelzmann Straße 9, 50931 Cologne, Germany. Phone: 49-221-4784803; Fax: 49-212-67002. E-mail: jan.brabender{at}t-online.de

Background and Aim: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the esophagus disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous esophagus epihelium of patients with Barrett's esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's disease.

Methods: Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis.

Results: A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RAR, RAR, RXR, RXRß, SPARC, TSPAN, and VEGF. Based on the expression signature of the normal appearing squamous esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%.

Conclusion: This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's esophagus disease. Based on the gene expression signature of the normal esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's esophagus disease.