Human Cancer Biology MicroRNA Expression Signatures in Barrett's Esophagus and Esophageal Adenocarcinoma

Purpose: Esophageal adenocarcinoma is a highly aggressive malignancy that frequently develops from Barrett's esophagus, a premalignant pathologic change occurring in the lower end of the esophagus. Identifying Barrett's esophagus patients at high risk of malignant transformation is essential to the prevention of esophageal adenocarcinoma. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of esophageal adenocarcinoma have not been extensively evaluated. Experimental Design: In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with Barrett's esophagus of either lowor high-grade dysplasia, or esophageal adenocarcinoma. Results: Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of Barrett's esophagus with high-grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for esophageal adenocarcinoma, but not for Barrett's esophagus with low-grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade-dysplasia Barrett's esophagus to esophageal adenocarcinoma. Conclusions: We showed that miRNAs were involved in the development and progression of esophageal adenocarcinoma. The identified significant miRNAs that may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer. (Clin Cancer Res 2009;15(18):5744–52) Esophageal cancer is the sixth most common cause of cancerassociated death worldwide (1). In the United States, especially in Caucasian males, both the incidence and the mortality of esophageal cancer have been steadily increasing during the past several decades (2, 3). Despite the wide application of radical esophagectomy and systemic chemoradiotherapy, the overall 5-year survival rate of esophageal cancer remains <20%, mainly due to the fact that a large proportion of patients are diagnosed at an advanced stage (2, 4). Therefore, it is critical for the control and treatment of this dreaded malignancy to identify clinically applicable biomarkers for early detection and targeted prevention. There are two major histologic types of esophageal cancer: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Esophageal adenocarcinoma is one of the fastest growing malignancies in the United States with a 6-fold increased incidence in the past three decades (3, 5, 6). Esophageal adenocarcinoma is usually associated with symptomatic gastroesophageal Authors' Affiliations: Departments of Epidemiology, Pathology, and Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China Received2/13/09; revised5/28/09; accepted 6/9/09; publishedOnlineFirst 9/8/09. Grant support: National Cancer Institute grant CA111922, The Premalignant Genome Atlas Program of the Duncan Family Institute for Cancer Prevention and Risk Assessment, a MRP grant from the University of Texas M.D. Anderson Cancer Center, and the Dallas, Cantu, Park, and Smith families, Rivercreek foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: Xifeng Wu, Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Blvd., Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-4657; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0385 5744 Clin Cancer Res 2009;15(18) September 15, 2009 www.aacrjournals.org Research. on April 16, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 8, 2009; DOI: 10.1158/1078-0432.CCR-09-0385