Evolution of DNA methylome from Barrett's esophagus to adenocarcinoma and their magnifying narrow-band imaging features

Strategy for identifying patients at risk for Barrett's esophageal cancer (BAC) is not established in Japan. DNA methylation is associated with various cancer types. We aimed to characterize the DNA methylome from Barrett's esophagus (BE) to BAC in the Japanese patients. We also explored magnifying narrow-band imaging (M-NBI) features of BE associated with epigenetic anomaly. Endoscopic biopsies were obtained from BE of cancer free subjects (n=50), BAC (n=21) and adjacent BE (n=27). Reduced representation bisulfite sequencing was performed to characterize genome-scale methylome signatures. Methylation of candidate genes were quantified by bisulfite pyrosequencing. M-NBI features of BE, where biopsies were obtained were investigated. Genome-scale methylation analysis demonstrated strikingly higher methylation levels at CpG islands in EAC and the adjacent BE compared to BE of cancer free subjects, for example, SLC16A12, DPYS, and N33 promoters (all P<0.05). NBI feature, such as demarcated oval/tubulovillous structure with coiled/wavy vessels was significantly associated with higher methylation of these promoters (all P<0.01). Multiple regression analysis demonstrated that both M-NBI feature (P=0.0005) and cancer occurrence (P<0.05) was independently associated with methylation status of non-neoplastic BE. Evolution of DNA methylome is an early event in the BAC, which may be promising biomarker. DNA methylation in BE can be also diagnosed endoscopically.