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Background: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. Methods: In a case-control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using Nano-String miRNA v2. We tested differences in detection by case group using the X² test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E-05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. Results: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but <20% of Barrett's esophagus. Seven miRNAs (miR-4286, miR-630, miR-575, miR-494, miR-320e, miR-4488, and miR-4508) exhibited the most extreme differences in expression with >5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case-control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. Conclusion: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. Impact: These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance. [ABSTRACT FROM AUTHOR]