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Novel DNA Methylation Biomarker Panel for Detection of Esophageal Adenocarcinoma and High-grade Dysplasia.

PURPOSE
Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high grade dysplasia (HGD) from normal squamous epithelium (SQ) or non-dysplastic BE (NDBE).


EXPERIMENTAL DESIGN
DNA methylation profiling of samples from SQ, NDBE, HGD and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfite-sequencing. Ultra-sensitive methylation-specific droplet digital PCR and NGS-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples.


RESULTS
Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared to SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a 4-marker panel (Model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples.


CONCLUSIONS
A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation based molecular assays holds promise for the detection of HGD/EAC using esophageal brushing samples.