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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