title: Candidate serum metabolite biomarkers for differentiating gastroesophageal reflux disease, Barrett's esophagus, and high-grade dysplasia/esophageal adenocarcinoma.
abstract: OBJECTIVE
  Incidence of esophageal adenocarcinoma (EA), an often fatal cancer, has increased sharply over recent decades. Several important risk factors (reflux, obesity, smoking) have been identified for EA and its precursor, Barrett's esophagus (BE), but a key challenge remains identifying individuals at highest risk, since most with reflux do not develop BE, and most with BE do not progress to cancer. Metabolomics represents an emerging approach for identifying novel biomarkers associated with cancer development.
  
  
  METHODS
  We used targeted liquid chromatography-mass spectrometry (LC-MS) to profile 57 metabolites in 322 serum specimens derived from individuals with gastroesophageal reflux disease (GERD), BE, high-grade dysplasia (HGD), or EA, drawn from two well-annotated epidemiologic parent studies.
  
  
  RESULTS
  Multiple metabolites differed significantly (P<0.05) between BE versus GERD (n=9), and between HGD/EA versus BE (n=4). Several top candidates (FDR q≤0.15), including urate, homocysteine, and 3-nitrotyrosine, are linked to inflammatory processes, which may contribute to BE/EA pathogenesis. Multivariate modeling achieved moderate discrimination between HGD/EA and BE (AUC=0.75), with less pronounced separation for BE versus GERD (AUC=0.64).
  
  
  CONCLUSIONS
  Serum metabolite differences can be detected between individuals with GERD versus BE, and between those with BE versus HGD/EA, and may help differentiate patients at different stages of progression to EA.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA; Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263 USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Buas
authors.affiliation: Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98109 USA.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98109 USA.
authors.forename: Danijel
authors.initials: D
authors.lastname: Djukovic
authors.affiliation: Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98109 USA.
authors.forename: Jiangjiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Onstad
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA; Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reid
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA; Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98109 USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109 USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, 98109 USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
keywords: Barrett’s esophagus; esophageal adenocarcinoma; gastroesophageal reflux disease; metabolomics; risk stratification; serum biomarkers