Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus

Prasad G Iyer, William R. Taylor, Michele L. Johnson, Ramona L. Lansing, Kristyn A. Maixner, Tracy C. Yab, Julie A. Simonson, Mary E. Devens, Seth W. Slettedahl, Douglas W. Mahoney, Calise K. Berger, Patrick H. Foote, Thomas Christopher Smyrk, Kenneth Ke Ning Wang, Herbert C. Wolfsen, David A. Ahlquist

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 Step 3: The capsule sponge was swallowed and withdrawn in 98% of subjects.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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalAmerican Journal of Gastroenterology
DOIs
StateAccepted/In press - Jun 12 2018

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Barrett Esophagus
Genetic Markers
Porifera
Capsules
ROC Curve
Area Under Curve
Esophagus
DNA
Deglutition
Methylation
Endoscopy
DNA Damage
Adenocarcinoma
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Iyer, P. G., Taylor, W. R., Johnson, M. L., Lansing, R. L., Maixner, K. A., Yab, T. C., ... Ahlquist, D. A. (Accepted/In press). Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus. American Journal of Gastroenterology, 1-11. https://doi.org/10.1038/s41395-018-0107-7

Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus. / Iyer, Prasad G; Taylor, William R.; Johnson, Michele L.; Lansing, Ramona L.; Maixner, Kristyn A.; Yab, Tracy C.; Simonson, Julie A.; Devens, Mary E.; Slettedahl, Seth W.; Mahoney, Douglas W.; Berger, Calise K.; Foote, Patrick H.; Smyrk, Thomas Christopher; Wang, Kenneth Ke Ning; Wolfsen, Herbert C.; Ahlquist, David A.

In: American Journal of Gastroenterology, 12.06.2018, p. 1-11.

Research output: Contribution to journalArticle

Iyer, PG, Taylor, WR, Johnson, ML, Lansing, RL, Maixner, KA, Yab, TC, Simonson, JA, Devens, ME, Slettedahl, SW, Mahoney, DW, Berger, CK, Foote, PH, Smyrk, TC, Wang, KKN, Wolfsen, HC & Ahlquist, DA 2018, 'Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus', American Journal of Gastroenterology, pp. 1-11. https://doi.org/10.1038/s41395-018-0107-7
Iyer, Prasad G ; Taylor, William R. ; Johnson, Michele L. ; Lansing, Ramona L. ; Maixner, Kristyn A. ; Yab, Tracy C. ; Simonson, Julie A. ; Devens, Mary E. ; Slettedahl, Seth W. ; Mahoney, Douglas W. ; Berger, Calise K. ; Foote, Patrick H. ; Smyrk, Thomas Christopher ; Wang, Kenneth Ke Ning ; Wolfsen, Herbert C. ; Ahlquist, David A. / Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus. In: American Journal of Gastroenterology. 2018 ; pp. 1-11.
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AU - Iyer, Prasad G

AU - Taylor, William R.

AU - Johnson, Michele L.

AU - Lansing, Ramona L.

AU - Maixner, Kristyn A.

AU - Yab, Tracy C.

AU - Simonson, Julie A.

AU - Devens, Mary E.

AU - Slettedahl, Seth W.

AU - Mahoney, Douglas W.

AU - Berger, Calise K.

AU - Foote, Patrick H.

AU - Smyrk, Thomas Christopher

AU - Wang, Kenneth Ke Ning

AU - Wolfsen, Herbert C.

AU - Ahlquist, David A.

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N2 - 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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