Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett's esophagus.
Abstract
We report a biomarker-based non-endoscopic method for detecting Barrett's esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the <i>CCNA1</i> locus. We tested <i>CCNA1</i> DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. <i>CCNA1</i> DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of <i>VIM</i> DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of <i>CCNA1</i> plus <i>VIM</i> DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of <i>CCNA1</i> plus <i>VIM</i> DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.
Biomarkers
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EDRN PI Authors
Medline Author List
- Barnholtz-Sloan JS
- Brock W
- Canto MI
- Chak A
- Chandar AK
- De la Cruz Cabrera O
- Dumot J
- Faulx A
- Guda K
- Iyer PG
- LaFramboise T
- Lutterbaugh JD
- Markowitz SD
- Moinova HR
- Shaheen NJ
- Thota PN
- Wang JS
- Willis JE