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Methylation Biomarker Panel Performance in Esophacap Cytology Samples for Diagnosing Barrett's Esophagus: A Double-Blind Prospective Validation Study

34 Pages Posted: 29 Nov 2018

See all articles by Zhixiong Wang

Zhixiong Wang

Sun Yat-Sen University (SYSU)

Swetha Kambhampati

University of California, San Francisco (UCSF) - UCSF Medical Center

Yulan Cheng

Johns Hopkins University - Division of Gastroenterology

John M. Abraham

Johns Hopkins University - Division of Gastroenterology

Xi Liu

Johns Hopkins University - Division of Gastroenterology

Ke Ma

Johns Hopkins University - Division of Gastroenterology

Alejandro Stark

Johns Hopkins University

Alexander Trick

Johns Hopkins University

Cem Simsek

Johns Hopkins University - Division of Gastroenterology

Tza-Huei Wang

Johns Hopkins University - Department of Medicine

Hua-Ling Tsai

Johns Hopkins University - Sidney Kimmel Comprehensive Cancer Center

Hao Wang

Johns Hopkins University - Sidney Kimmel Comprehensive Cancer Center

Yulong He

Sun Yat-Sen University (SYSU)

Mouen A. Khashab

Johns Hopkins University - Division of Gastroenterology

Eun Ji Shin

Johns Hopkins University - Division of Gastroenterology

Saowanee Ngamruengphong

Johns Hopkins University - Division of Gastroenterology

Stephen Meltzer

Johns Hopkins University - Division of Gastroenterology

More...

Abstract

Background: Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). Current guidelines recommend endoscopic screening of patients with two or more potential BE risk factors but fail to capture two-thirds of prevalent BE cases. Given the lack of an acceptable, accurate and cost-effective tool for BE screening, new methods are needed to allow population-based screening. Here, we sought to develop a BE screening method based on methylation status in cytology samples captured by EsophaCap, a retrievable sponge sampling device, using a streamlined sensitive technique, methylation on beads (MOB).

Methods: We conducted a double-blinded, prospective cohort study. 173 participants, meeting inclusion criteria, were enrolled, 80 of whom completed the study and were included in statistical analyses. We employed MOB to extract and bisulfite-convert DNA, then qMSP to assess methylation of 8 candidate genes. Lasso regression was applied to establish a prediction model for BE diagnosis.

Findings: 85% (147/173) of participants were able to swallow the EsophaCap. In the training set, 5 of 8 candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in the BE group than the control group. In a training set of EsophaCap samples, a 4-biomarker-plus-age lasso regression model showed high accuracy of BE diagnosis: AUC was 0.894, with sensitivity 94.4% (95%CI 0.71%~99%) and specificity 62.2% (95%CI 44.6%~77.3%). The lasso model also performed well in an independent test set: AUC=0.857 (p=0.001), with sensitivity=85.7% (95%CI 56.2%~97.5%) and specificity=92.8% (95%CI 64.1%~99.6%).

Interpretation: EsophaCap, in combination with an epigenetic biomarker panel and MOB, is a promising, well-tolerated, low-cost esophageal sampling strategy for BE diagnosis. This approach merits further prospective studies in larger populations.

Funding Statement: National Institutes of Health (Grants: CA211457, DK118250) and a Discovery Award from The Johns Hopkins University School of Medicine.

Declaration of Interests: All authors state that there are no conflicts of interest.

Ethics Approval Statement: This study was approved by the JHM IRB.

Keywords: Barrett's Esophagus, Cytologic sampling, methylation, biomarkers, methylation on beads, Lasso regression

Suggested Citation

Wang, Zhixiong and Kambhampati, Swetha and Cheng, Yulan and Abraham, John M. and Liu, Xi and Ma, Ke and Stark, Alejandro and Trick, Alexander and Simsek, Cem and Wang, Tza-Huei and Tsai, Hua-Ling and Wang, Hao and He, Yulong and Khashab, Mouen A. and Shin, Eun Ji and Ngamruengphong, Saowanee and Meltzer, Stephen, Methylation Biomarker Panel Performance in Esophacap Cytology Samples for Diagnosing Barrett's Esophagus: A Double-Blind Prospective Validation Study (August 26, 2018). Available at SSRN: https://ssrn.com/abstract=3244951

Zhixiong Wang

Sun Yat-Sen University (SYSU)

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Swetha Kambhampati

University of California, San Francisco (UCSF) - UCSF Medical Center

505 Parnassus Ave
San Francisco, CA 94143
United States

Yulan Cheng

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

John M. Abraham

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Xi Liu

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Ke Ma

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Alejandro Stark

Johns Hopkins University

Baltimore, MD 20036-1984
United States

Alexander Trick

Johns Hopkins University

Baltimore, MD 20036-1984
United States

Cem Simsek

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Tza-Huei Wang

Johns Hopkins University - Department of Medicine

720 Rutland Avenue
Baltimore, MD 21205-2196
United States

Hua-Ling Tsai

Johns Hopkins University - Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD 20036-1984
United States

Hao Wang

Johns Hopkins University - Sidney Kimmel Comprehensive Cancer Center

Baltimore, MD 20036-1984
United States

Yulong He

Sun Yat-Sen University (SYSU)

135, Xingang Xi Road
Guangzhou, Guangdong 510275
China

Mouen A. Khashab

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Eun Ji Shin

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Saowanee Ngamruengphong

Johns Hopkins University - Division of Gastroenterology

Baltimore, MD
United States

Stephen Meltzer (Contact Author)

Johns Hopkins University - Division of Gastroenterology ( email )

Baltimore, MD
United States

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