Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma

Andrew Kalra; Ke Ma; Yulan Cheng; Hua Ling Tsai; Hao Wang; Leslie Cope; Yifan Yang; Daniel Lunz; Sarah Laun; Lisa Kann; Simran Jit; Yousra Ahmed; Shayan Gheshlaghi; Alan H. Tieu; Vincent Castillo; Russell Hales; Josephine Feliciano; Vincent Lam; Kristin Marrone; Ken Hui; Michelle Ma; Robert Hughes; Venkata Akshintala; Kathy Bull-Henry; Jinny Ha; Karim Boudadi; Zacharia H. Foda; Richard Battaforano; Mouen Khashab; Eun Ji Shin; Olaya Brewer; Saowanee Ngamruengphong; Rachel Ganster; Blair A. Jobe; Pauline Zellenrath; Manon Spaander; Ali H. Zaidi; Stephen J. Meltzer

doi:10.14309/ajg.0000000000003323

Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma

Andrew Kalra, Ke Ma, Yulan Cheng, Hua Ling Tsai, Hao Wang, Leslie Cope, Yifan Yang, Daniel Lunz, Sarah Laun, Lisa Kann, Simran Jit, Yousra Ahmed, Shayan Gheshlaghi, Alan H. Tieu, Vincent Castillo, Russell Hales, Josephine Feliciano, Vincent Lam, Kristin Marrone, Ken HuiMichelle Ma, Robert Hughes, Venkata Akshintala, Kathy Bull-Henry, Jinny Ha, Karim Boudadi, Zacharia H. Foda, Richard Battaforano, Mouen Khashab, Eun Ji Shin, Olaya Brewer, Saowanee Ngamruengphong, Rachel Ganster, Blair A. Jobe, Pauline Zellenrath, Manon Spaander, Ali H. Zaidi, Stephen J. Meltzer^*

^*Corresponding author for this work

Gastroenterology & Hepatology

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background and Aims:

We sought to develop a minimally-invasive, robust, accessible nonendoscopic strategy to diagnose Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and its immediate precursor lesion, high-grade dysplasia (HGD) based on methylated DNA biomarkers applied to a retrievable sponge-capsule device in a cohort representative of the BE population (i.e., mostly short-segment, non-dysplastic BE, NDBE).

Methods:

We identified 12 candidate methylation markers to distinguish normal vs. abnormal esophagus. These 12 markers were first assayed in 21-paired matched NDBE-normal esophageal tissues, then assessed in a case-control study of 234 esophageal samples collected using a sponge-capsule device. A classification algorithm was developed using Least Absolute Shrinkage and Selection Operator (LASSO) in a 199-patient training set and tested in an independent 35-patient test set.

Results:

Twelve markers (A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30, and USP44) were significantly hypermethylated (i.e., all P<0.05) in BE vs. matched normal esophageal biopsies. A discriminatory three-gene LASSO panel (USP44, TBCD1D30, NELL1), adjusted for age and sex, accurately distinguished HGD or EAC from normal control patients in both training (AUC=0.911, 95%CI=0.863-0.959) and test (AUC=0.969, 95%CI=0.911-1.00) sets. In normal vs. NDBE/LGD/HGD/EAC patients, this algorithm exhibited AUCs of 0.862 (95%CI=0.812-0.912) and 0.864 (95%CI=0.745-0.982) in training and test sets, respectively. In normal vs. NDBE patients, the algorithm yielded AUCs of 0.819 (95%CI=0.748-0.889) and 0.776 (95%CI=0.583-0.968) in training and test sets, respectively.

Conclusions:

This discriminatory biomarker panel algorithm exemplifies a practical nonendoscopic strategy to diagnose BE, HGD, and EAC using a minimally-invasive sponge-capsule device coupled with DNA methylation markers.

Original language	English
Article number	10.14309/ajg.0000000000003323
Journal	American Journal of Gastroenterology
DOIs	https://doi.org/10.14309/ajg.0000000000003323
Publication status	E-pub ahead of print - 17 Jan 2025

Bibliographical note

Publisher Copyright:
Copyright © 2025 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.

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10.14309/ajg.0000000000003323

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Kalra, A., Ma, K., Cheng, Y., Tsai, H. L., Wang, H., Cope, L., Yang, Y., Lunz, D., Laun, S., Kann, L., Jit, S., Ahmed, Y., Gheshlaghi, S., Tieu, A. H., Castillo, V., Hales, R., Feliciano, J., Lam, V., Marrone, K., ... Meltzer, S. J. (2025). Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma. American Journal of Gastroenterology, Article 10.14309/ajg.0000000000003323. Advance online publication. https://doi.org/10.14309/ajg.0000000000003323

@article{79cffb42e64249139b6546faad1ee43a,

title = "Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma",

abstract = "Background and Aims:We sought to develop a minimally-invasive, robust, accessible nonendoscopic strategy to diagnose Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and its immediate precursor lesion, high-grade dysplasia (HGD) based on methylated DNA biomarkers applied to a retrievable sponge-capsule device in a cohort representative of the BE population (i.e., mostly short-segment, non-dysplastic BE, NDBE).Methods:We identified 12 candidate methylation markers to distinguish normal vs. abnormal esophagus. These 12 markers were first assayed in 21-paired matched NDBE-normal esophageal tissues, then assessed in a case-control study of 234 esophageal samples collected using a sponge-capsule device. A classification algorithm was developed using Least Absolute Shrinkage and Selection Operator (LASSO) in a 199-patient training set and tested in an independent 35-patient test set.Results:Twelve markers (A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30, and USP44) were significantly hypermethylated (i.e., all P<0.05) in BE vs. matched normal esophageal biopsies. A discriminatory three-gene LASSO panel (USP44, TBCD1D30, NELL1), adjusted for age and sex, accurately distinguished HGD or EAC from normal control patients in both training (AUC=0.911, 95%CI=0.863-0.959) and test (AUC=0.969, 95%CI=0.911-1.00) sets. In normal vs. NDBE/LGD/HGD/EAC patients, this algorithm exhibited AUCs of 0.862 (95%CI=0.812-0.912) and 0.864 (95%CI=0.745-0.982) in training and test sets, respectively. In normal vs. NDBE patients, the algorithm yielded AUCs of 0.819 (95%CI=0.748-0.889) and 0.776 (95%CI=0.583-0.968) in training and test sets, respectively.Conclusions:This discriminatory biomarker panel algorithm exemplifies a practical nonendoscopic strategy to diagnose BE, HGD, and EAC using a minimally-invasive sponge-capsule device coupled with DNA methylation markers.",

author = "Andrew Kalra and Ke Ma and Yulan Cheng and Tsai, {Hua Ling} and Hao Wang and Leslie Cope and Yifan Yang and Daniel Lunz and Sarah Laun and Lisa Kann and Simran Jit and Yousra Ahmed and Shayan Gheshlaghi and Tieu, {Alan H.} and Vincent Castillo and Russell Hales and Josephine Feliciano and Vincent Lam and Kristin Marrone and Ken Hui and Michelle Ma and Robert Hughes and Venkata Akshintala and Kathy Bull-Henry and Jinny Ha and Karim Boudadi and Foda, {Zacharia H.} and Richard Battaforano and Mouen Khashab and Shin, {Eun Ji} and Olaya Brewer and Saowanee Ngamruengphong and Rachel Ganster and Jobe, {Blair A.} and Pauline Zellenrath and Manon Spaander and Zaidi, {Ali H.} and Meltzer, {Stephen J.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.",

year = "2025",

month = jan,

day = "17",

doi = "10.14309/ajg.0000000000003323",

language = "English",

journal = "American Journal of Gastroenterology",

issn = "0002-9270",

publisher = "Wolters Kluwer Health",

}

Kalra, A, Ma, K, Cheng, Y, Tsai, HL, Wang, H, Cope, L, Yang, Y, Lunz, D, Laun, S, Kann, L, Jit, S, Ahmed, Y, Gheshlaghi, S, Tieu, AH, Castillo, V, Hales, R, Feliciano, J, Lam, V, Marrone, K, Hui, K, Ma, M, Hughes, R, Akshintala, V, Bull-Henry, K, Ha, J, Boudadi, K, Foda, ZH, Battaforano, R, Khashab, M, Shin, EJ, Brewer, O, Ngamruengphong, S, Ganster, R, Jobe, BA, Zellenrath, P , Spaander, M, Zaidi, AH & Meltzer, SJ 2025, 'Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma', American Journal of Gastroenterology. https://doi.org/10.14309/ajg.0000000000003323

TY - JOUR

T1 - Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma

AU - Kalra, Andrew

AU - Ma, Ke

AU - Cheng, Yulan

AU - Tsai, Hua Ling

AU - Wang, Hao

AU - Cope, Leslie

AU - Yang, Yifan

AU - Lunz, Daniel

AU - Laun, Sarah

AU - Kann, Lisa

AU - Jit, Simran

AU - Ahmed, Yousra

AU - Gheshlaghi, Shayan

AU - Tieu, Alan H.

AU - Castillo, Vincent

AU - Hales, Russell

AU - Feliciano, Josephine

AU - Lam, Vincent

AU - Marrone, Kristin

AU - Hui, Ken

AU - Ma, Michelle

AU - Hughes, Robert

AU - Akshintala, Venkata

AU - Bull-Henry, Kathy

AU - Ha, Jinny

AU - Boudadi, Karim

AU - Foda, Zacharia H.

AU - Battaforano, Richard

AU - Khashab, Mouen

AU - Shin, Eun Ji

AU - Brewer, Olaya

AU - Ngamruengphong, Saowanee

AU - Ganster, Rachel

AU - Jobe, Blair A.

AU - Zellenrath, Pauline

AU - Spaander, Manon

AU - Zaidi, Ali H.

AU - Meltzer, Stephen J.

PY - 2025/1/17

Y1 - 2025/1/17

N2 - Background and Aims:We sought to develop a minimally-invasive, robust, accessible nonendoscopic strategy to diagnose Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and its immediate precursor lesion, high-grade dysplasia (HGD) based on methylated DNA biomarkers applied to a retrievable sponge-capsule device in a cohort representative of the BE population (i.e., mostly short-segment, non-dysplastic BE, NDBE).Methods:We identified 12 candidate methylation markers to distinguish normal vs. abnormal esophagus. These 12 markers were first assayed in 21-paired matched NDBE-normal esophageal tissues, then assessed in a case-control study of 234 esophageal samples collected using a sponge-capsule device. A classification algorithm was developed using Least Absolute Shrinkage and Selection Operator (LASSO) in a 199-patient training set and tested in an independent 35-patient test set.Results:Twelve markers (A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30, and USP44) were significantly hypermethylated (i.e., all P<0.05) in BE vs. matched normal esophageal biopsies. A discriminatory three-gene LASSO panel (USP44, TBCD1D30, NELL1), adjusted for age and sex, accurately distinguished HGD or EAC from normal control patients in both training (AUC=0.911, 95%CI=0.863-0.959) and test (AUC=0.969, 95%CI=0.911-1.00) sets. In normal vs. NDBE/LGD/HGD/EAC patients, this algorithm exhibited AUCs of 0.862 (95%CI=0.812-0.912) and 0.864 (95%CI=0.745-0.982) in training and test sets, respectively. In normal vs. NDBE patients, the algorithm yielded AUCs of 0.819 (95%CI=0.748-0.889) and 0.776 (95%CI=0.583-0.968) in training and test sets, respectively.Conclusions:This discriminatory biomarker panel algorithm exemplifies a practical nonendoscopic strategy to diagnose BE, HGD, and EAC using a minimally-invasive sponge-capsule device coupled with DNA methylation markers.

AB - Background and Aims:We sought to develop a minimally-invasive, robust, accessible nonendoscopic strategy to diagnose Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and its immediate precursor lesion, high-grade dysplasia (HGD) based on methylated DNA biomarkers applied to a retrievable sponge-capsule device in a cohort representative of the BE population (i.e., mostly short-segment, non-dysplastic BE, NDBE).Methods:We identified 12 candidate methylation markers to distinguish normal vs. abnormal esophagus. These 12 markers were first assayed in 21-paired matched NDBE-normal esophageal tissues, then assessed in a case-control study of 234 esophageal samples collected using a sponge-capsule device. A classification algorithm was developed using Least Absolute Shrinkage and Selection Operator (LASSO) in a 199-patient training set and tested in an independent 35-patient test set.Results:Twelve markers (A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30, and USP44) were significantly hypermethylated (i.e., all P<0.05) in BE vs. matched normal esophageal biopsies. A discriminatory three-gene LASSO panel (USP44, TBCD1D30, NELL1), adjusted for age and sex, accurately distinguished HGD or EAC from normal control patients in both training (AUC=0.911, 95%CI=0.863-0.959) and test (AUC=0.969, 95%CI=0.911-1.00) sets. In normal vs. NDBE/LGD/HGD/EAC patients, this algorithm exhibited AUCs of 0.862 (95%CI=0.812-0.912) and 0.864 (95%CI=0.745-0.982) in training and test sets, respectively. In normal vs. NDBE patients, the algorithm yielded AUCs of 0.819 (95%CI=0.748-0.889) and 0.776 (95%CI=0.583-0.968) in training and test sets, respectively.Conclusions:This discriminatory biomarker panel algorithm exemplifies a practical nonendoscopic strategy to diagnose BE, HGD, and EAC using a minimally-invasive sponge-capsule device coupled with DNA methylation markers.

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U2 - 10.14309/ajg.0000000000003323

DO - 10.14309/ajg.0000000000003323

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AN - SCOPUS:85216409069

SN - 0002-9270

JO - American Journal of Gastroenterology

JF - American Journal of Gastroenterology

M1 - 10.14309/ajg.0000000000003323

ER -

Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma

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