Florin M. Selaru¹, Suna Wang², Jing Yin², Karsten Schulmann³, Yan Xu², Yuriko Mori¹, Alexandru V. Olaru¹, Fumiaki Sato¹, James P. Hamilton¹, John M. Abraham¹, Paul Schneider⁴, Bruce D. Greenwald², Jan Brabender⁴ and Stephen J. Meltzer¹

¹Gastroenterology Division, Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD 21231. ²Gastroenterology Division, Department of Medicine, University of Maryland School of Medicine and Baltimore VA Hospital and Greenebaum Cancer Center, Baltimore, MD 21201. ³Division of Gastroenterology, Department of Medicine, Ruhr-University Bochum, Bochum, Germany. ⁴Department of Visceral and Vascular Surgery, University of Cologne, Germany.

Abstract

Background and Aims: Because of the extremely low neoplastic progression rate in Barrett’s esophagus, it is difficult to diagnose patients with concomitant adenocarcinoma early in their disease course. If biomarkers existed in normal squamous esophageal epithelium to identify patients with concomitant esophageal adenocarcinoma, potential applications would be far-reaching. The aim of the current study was to identify global gene expression patterns in normal esophageal epithelium capable of revealing simultaneous esophageal adenocarcinoma, even located remotely in the esophagus.

Methods: Tissues comprised normal esophageal epithelia from 9 patients with esophageal adenocarcinoma, 8 patients lacking esophageal adenocarcinoma or Barrett’s, and 6 patients with Barrett’s esophagus alone. cDNA microarrays were performed, and pattern recognition in each of these subgroups was achieved using shrunken nearest centroid predictors.

Results: Our method accurately discriminated normal esophageal epithelia of 8/8 patients without esophageal adenocarcinoma or Barrett’s esophagus and of 6/6 patients with Barrett’s esophagus alone from normal esophageal epithelia of 9/9 patients with Barrett’s esophagus and concomitant esophageal adenocarcinoma. Moreover, we identified genes differentially expressed between the above subgroups. Thus, based on their corresponding normal esophageal epithelia alone, our method accurately diagnosed patients who had concomitant esophageal adenocarcinoma.

Conclusions: These global gene expression patterns, along with individual genes culled from them, represent potential biomarkers for the early diagnosis of esophageal adenocarcinoma from normal esophageal epithelia. Genes discovered in normal esophagus that are differentially expressed in patients with vs. without esophageal adenocarcinoma merit further pursuit in molecular genetic, functional, and therapeutic interventional studies.