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Expression Analysis of Barrett's Esophagus–Associated High-Grade Dysplasia in Laser Capture Microdissected Archival Tissue

Authors' Affiliations: Departments of ¹ Pathology and ² Medicine, Rhode Island Hospital/Brown University, Providence, Rhode Island; ³ Department of Pathology, Oregon Health and Science University, Portland, Oregon; and ⁴ Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts

Requests for reprints: Murray B. Resnick, Department of Pathology, Rhode Island Hospital, APC12, 593 Eddy Street, Providence, RI 02903. Phone: 401-444-4380; Fax: 401-444-8514; E-mail: mresnick{at}lifespan.org.

Purpose: Identifying genes differentially expressed in nondysplastic BE (NDBE) from those expressed in high-grade dysplasia (HGD) should be of value in improving our understanding of this transition and may yield new diagnostic and/or prognostic markers. The aim of this study was to determine the differential transcriptome of HGD compared with NDBE through gene microarray analysis of epithelial cells microdissected from archival tissue specimens.

Experimental Design: Laser capture microdissection was used to isolate epithelial cells from adjacent inflammatory and stromal cells. Epithelial mRNA was extracted from areas of NDBE and HGD in matched biopsies from 11 patients. mRNA was reverse transcribed and applied on Affymetrix cDNA microarray chips customized for formalin-exposed tissue. For a subset of these genes, differential gene expression was confirmed by real-time PCR and immunohistochemistry.

Results: There were 131 genes overexpressed by at least 2.5-fold in HGD versus NDBE and 16 genes that were underexpressed by at least 2.5-fold. Among the overexpressed genes are several previously shown to be increased in the neoplastic progression of BE, as well as novel genes such as lipocalin-2, S100A9, matrix metallopeptidase 12, secernin 1, and topoisomerase II. Genes decreased in dysplastic epithelium include MUC5AC, trefoil factor 1 (TFF1), meprin A, and CD13. Real-time PCR validated the changes in expression in 24 of 28 selected genes. Immunohistochemistry confirmed increased protein expression for topoisomerase II, S100A9, and lipocalin-2 and decreased expression of TFF1 across the spectrum of BE-associated dysplasia from NDBE through adenocarcinoma.

Conclusions: This is the first study to identify epithelial genes differentially expressed in HGD versus NDBE in matched patient samples. The genes identified include several previously implicated in the pathogenesis of BE-associated dysplasia and new candidates for further investigation.