ARTICLE: Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study

AUTHORS: Zhixiong Wang, Swetha Kambhampati, Yulan Cheng, Ke MaCem Simsek, Alan H Tieu, John M Abraham, Xi Liu, Vishnu Prasath, Mark D Duncan, Alejandro Stark, Alexander Trick, Hua-Ling Tsai, Hao Wang, Yulong He, Mouen A Khashab, Saowanee Ngamruengphong, Eun J Shin, Tza-Huei Wang and Stephen J. Meltzer

JOURNAL: Clin Cancer Res. 2019 Jan 22. pii: clincanres.3696.2018. doi: 10.1158/1078-0432.CCR-18-3696. [Epub ahead of print]


PURPOSE: Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for BE diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a BE detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB).

EXPERIMENTAL DESIGN: We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We employed MOB to extract and bisulfite-convert DNA, followed by qMSP to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set.

RESULTS: In the training set, 5 of 8 candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in BE patients than in controls. We built a 4-biomarker-plus-age lasso regression model for BE diagnosis. The AUC was 0.894, with sensitivity 94.4% (95% CI 71%~99%) and specificity 62.2% (95% CI 44.6%~77.3%) in the training set. This model also performed with high accuracy for BE diagnosis in an independent test set: AUC= 0.929 (P<0.001, 95% CI 0.810~1), with sensitivity = 78.6% (95% CI 48.8%~94.3%) and specificity = 92.8% (95% CI 64.1%~99.6%).

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

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