Subjects

Abstract

BACKGROUND

Minimally invasive methods have been described to detect Barrett’s esophagus (BE), but are limited by subjectivity and suboptimal accuracy. We identified methylated DNA markers (MDMs) for BE in tissue and assessed their accuracy on whole esophagus brushings and capsule sponge samples.

Methods

Step 1: Unbiased whole methylome sequencing was performed on DNA from BE and normal squamous esophagus (SE) tissue. Discriminant MDM candidates were validated on an independent patient cohort (62 BE cases, 30 controls) by quantitative methylation specific PCR (qMSP). Step 2: Selected MDMs were further evaluated on whole esophageal brushings (49 BE cases, 36 controls). 35 previously sequenced esophageal adenocarcinoma (EAC) MDMs were also evaluated. Step 3: 20 BE cases and 20 controls were randomized to swallow capsules sponges (25 mm, 10 pores or 20 pores per inch (ppi)) followed endoscopy. DNA yield, tolerability, and mucosal injury were compared. Best MDM assays were performed on this cohort.

Results

Step 1: 19 MDMs with areas under the ROC curve (AUCs) >0.85 were carried forward. Step 2: On whole esophageal brushings, 80% of individual MDM candidates showed high accuracy for BE (AUCs 0.84–0.94). Step 3: The capsule sponge was swallowed and withdrawn in 98% of subjects. Tolerability was superior with the 10 ppi sponge with minimal mucosal injury and abundant DNA yield. A 2-marker panel (VAV3+ZNF682) yielded excellent BE discrimination (AUC = 1).

Conclusions

Identified MDMs discriminate BE with high accuracy. BE detection appears safe and feasible with a capsule sponge. Corroboration in larger studies is warranted. ClinicalTrials.gov number NCT02560623.

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Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    • Prasad G. Iyer MD, MSc
    • , William R. Taylor MS
    • , Michele L. Johnson CCRP
    • , Ramona L. Lansing RN
    • , Kristyn A. Maixner APRN
    • , Tracy C. Yab MBA
    • , Julie A. Simonson CCRP
    • , Mary E. Devens RN
    • , Calise K. Berger BS
    • , Patrick H. Foote BS
    • , Kenneth K. Wang MD
    •  & David A. Ahlquist MD
  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    • Seth W. Slettedahl BS
    •  & Douglas W. Mahoney MS
  3. Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA

    • Thomas C. Smyrk MD
  4. Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA

    • Herbert C. Wolfsen MD

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Guarantor of the article

PGI.

Specific author contributions

Study concept and design: PGI, DAA, SWS, DWM. Acquisition of data: RL, MLJ, KAM, TCY, JAS, MED, CKB, PHF, WRT, TCS. Analysis and interpretation of data: WRT, SWS, DWM, PGI, DAA. Drafting the manuscript: PGI. Critical revision of manuscript for important intellectual content: PGI, WRT, KKW, DAK, DAA, HW. Obtained Funding, Study Supervision: PGI, DAA.

Financial support

Supported in part by Exact Sciences.

Potential competing interests

PGI: Research funding from Exact Sciences, C2 Therapeutics, Intromedic Inc, Consultant Medtronic, Symple Surgical. MLJ: None. RL: None. KAM: None. JAS: None. MED: None. SWS: None. CKB: None. PHF: None. TCS: None. HW: Research funding from Exact Sciences and Nine Point Medical. KKW: Research funding from Nine Point Medical, C2 therapeutics, Olympus, Medtronic, Boston Scientific. DAA: Research funding from Exact Sciences, Scientific advisor to Exact Sciences. Mayo Clinic is a minor equity investor in Exact Sciences. DAA, WRT, DWM, and TCY are co-inventors on technology licensed to Exact Sciences.

Corresponding author

Correspondence to Prasad G. Iyer MD, MSc.

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DOI

https://doi.org/10.1038/s41395-018-0107-7

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