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Candidate serum metabolite biomarkers for differentiating gastroesophageal reflux disease, Barrett’s esophagus, and high-grade dysplasia/esophageal adenocarcinoma

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Abstract

Introduction/objectives

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 in 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).

Conclusion

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.

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Acknowledgements

We thank Terri Watson, Tricia Christopherson, Paul Hansen, Jessica Arnaudo, David Cowan, and Carissa Sanchez for their contributions in project management, organization of biospecimens/data, or assistance with data retrieval. This work was principally supported by NIH grant R21CA178621 (T.L.V. and D.R.) and NIH training grant T32CA009168 (T.L.V). Additional support was provided by NIH grants K05CA124911 (T.L.V.), P01CA091955 (B.J.R), and 5P30CA015704 (D.R.).

Author contributions

Conception and design: M.F.B., T.L.V., D.R. Subject recruitment: T.L.V., B.J.R. Data acquisition: H.G., D.D., J.Z. Analysis and interpretation of data: M.F.B, H.G., D.D., L.O., D.R., T.L.V. Drafting of the manuscript: M.F.B., T.L.V., H.G., D.R. Study supervision: D.R., T.L.V. All authors critically revised the manuscript for intellectual content.

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Authors and Affiliations

  1. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Matthew F. Buas, Lynn Onstad, Brian J. Reid, Daniel Raftery & Thomas L. Vaughan

  2. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Matthew F. Buas

  3. Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA

    Haiwei Gu, Danijel Djukovic, Jiangjiang Zhu & Daniel Raftery

  4. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Brian J. Reid

  5. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, 98109, USA

    Thomas L. Vaughan

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  1. Matthew F. Buas
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  3. Danijel Djukovic
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Correspondence to Daniel Raftery or Thomas L. Vaughan.

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Conflict of interest

D.R. holds equity and an executive role in Matrix‑Bio, Inc. (IN, USA). The authors have no other potential conflicts of interest to disclose.

Compliance with ethical requirements

All authors complied with ethical policies as described. Potential conflicts of interests were disclosed. This study included human participants and was approved by the Institutional Review Board at the Fred Hutchinson Cancer Research Center. Appropriate informed consent was obtained.

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Buas, M.F., Gu, H., Djukovic, D. et al. Candidate serum metabolite biomarkers for differentiating gastroesophageal reflux disease, Barrett’s esophagus, and high-grade dysplasia/esophageal adenocarcinoma. Metabolomics 13, 23 (2017). https://doi.org/10.1007/s11306-016-1154-y

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