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Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

The poor prognosis and rising incidence of esophageal adenocarcinoma highlight the need for improved detection methods. The potential for circulating microRNAs (miRNAs) as biomarkers in other cancers has been shown, but circulating miRNAs have not been well characterized in esophageal adenocarcinoma. We investigated whether circulating exosomal miRNAs have potential to discriminate individuals with esophageal adenocarcinoma from healthy controls and non-dysplastic Barrett’s esophagus.

Methods

Seven hundred fifty-eight miRNAs were profiled in serum circulating exosomes from a cohort of 19 healthy controls, 10 individuals with Barrett’s esophagus, and 18 individuals with locally advanced esophageal adenocarcinoma. MiRNA expression was assessed using all possible permutations of miRNA ratios per individual. Four hundred eight miRNA ratios were differentially expressed in individuals with cancer compared to controls and Barrett’s esophagus (Mann-Whitney U test, P < 0.05). The 179/408 ratios discriminated esophageal adenocarcinoma from healthy controls and Barrett’s esophagus (linear regression, P < 0.05; area under receiver operating characteristic (ROC) > 0.7, P < 0.05). A multi-biomarker panel (RNU6-1/miR-16-5p, miR-25-3p/miR-320a, let-7e-5p/miR-15b-5p, miR-30a-5p/miR-324-5p, miR-17-5p/miR-194-5p) demonstrated enhanced specificity and sensitivity (area under ROC = 0.99, 95 % CI 0.96–1.0) over single miRNA ratios to distinguish esophageal adenocarcinoma from controls and Barrett’s esophagus.

Conclusions

This study highlights the potential for serum exosomal miRNAs as biomarkers for the detection of esophageal adenocarcinoma.

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Author Contributions

All authors participated in aspects of study design, data acquisition and analysis, and preparation of the manuscript.

Funding

This work was supported by a Project grant (APP1022720) and a Centres of Research Excellence grant (APP1040947), both awarded by the National Health and Medical Research Council of Australia, and a Strategic Research Partnership Grant awarded by the Cancer Council of New South Wales.

Author information

Authors and Affiliations

  1. Department of Surgery, Flinders University, Room 3D211, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, 5042, Australia

    Karen Chiam, Tingting Wang, David I. Watson, George C. Mayne, Tanya S. Irvine, Tim Bright, Lorelle Smith & Damian J. Hussey

  2. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    Imogen A. White

  3. University of Adelaide School of Medical Sciences, Adelaide, South Australia, Australia

    Joanne M. Bowen

  4. Royal Adelaide Hospital Cancer Centre, Adelaide, South Australia, Australia

    Dorothy Keefe

  5. Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia

    Lorelle Smith & Sarah K. Thompson

  6. Department of Anaesthesia and Pain Medicine, Flinders University, Adelaide, South Australia, Australia

    Michael E. Jones

  7. Department of Anatomy and Histology, Flinders University, Adelaide, South Australia, Australia

    Michael E. Jones

Authors
  1. Karen Chiam
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  2. Tingting Wang
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  3. David I. Watson
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  4. George C. Mayne
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  5. Tanya S. Irvine
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  6. Tim Bright
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  7. Lorelle Smith
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  8. Imogen A. White
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  9. Joanne M. Bowen
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  10. Dorothy Keefe
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  11. Sarah K. Thompson
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  12. Michael E. Jones
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  13. Damian J. Hussey
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Corresponding author

Correspondence to Damian J. Hussey.

Electronic supplementary material

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Supplementary Table 1

Predicted probability that each left-out patient in the leave-one-out cross validation has cancer. Each probability was determined using a regression model of a five miRNA ratio panel derived with the sequential testing method utilized in this study. Out of the 18 actual cancer patients in the cohort, the leave-one-out cross validation correctly identified 13 cancer patients from the 18 individuals (highlighted in gray) with the highest predicted probabilities of being a cancer based on the regression model. (DOC 69 kb)

Supplementary Figure 1

Distribution (a) and normality plots (b) of the standardized residuals of the combined five miRNA ratios biomarker panel. (DOC 89 kb)

Supplementary Figure 2

Distribution of the five miRNA ratios in healthy controls, Barrett’s esophagus and esophageal adenocarcinoma. (DOC 395 kb)

Supplementary Figure 3

LOOCV prediction errors for increasing numbers of ratios in the final regression model. Error rate is the number of cancers that were misclassified, as a percentage. (DOC 59 kb)

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Chiam, K., Wang, T., Watson, D.I. et al. Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma. J Gastrointest Surg 19, 1208–1215 (2015). https://doi.org/10.1007/s11605-015-2829-9

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  • DOI: https://doi.org/10.1007/s11605-015-2829-9

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