Abstract
To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. Identifying patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma remains a challenge. Previous studies have demonstrated the potential utility of epigenetic markers for identifying this group. A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with nondysplastic Barrett esophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. In all, 12 patients with "progressive" versus 12 with "nonprogressive" nondysplastic Barrett esophagus were analyzed via methylation array. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumor suppressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors 67.8% vs 96.7% in nonprogressors; P = 0.0001, z = 3.85, Wilcoxon rank-sum test) and was associated with the progression to adenocarcinoma. There were no differences in copy number between the 2 groups, but a global trend towards hypomethylation in the progressor group was observed. Hypomethylation of OR3A4 has the ability to risk stratify the patient with nondysplastic Barrett esophagus and may form the basis of a future surveillance program.
Highlights
We have identified that hypomethylation at cg09890332 corresponding to the CG nucleotide at position (CHR) of OR3A4 can discriminate between patients who progress from nondysplastic Barrett esophagus (BE) and those who did not
This association is maintained across independent cohorts, and seems to be related temporally, and by case status
The effect of hypomethylation on the OR3A4 gene seems to be functional, in that immunohistochemistry reveals an increase in OR3A4 expression in samples with hypomethylation
Summary
To investigate differences in methylation between patients with nondysplastic Barrett esophagus who progress to invasive adenocarcinoma and those who do not. Forty-four methylation markers were identified that may be able to discriminate between nondysplastic Barrett esophagus that either progress to adenocarcinoma or remain static. The pathological changes seen in Barrett adenocarcinoma are understood as part of a well-established metaplasiadysplasia-carcinoma sequence,[15] the molecular drivers are less clear.[16,17,18] The current dilemma is that for patients with nondysplastic BE, there are no accurate methods for identifying the small number of patients at high risk of progression to cancer. The study aims to determine whether there are differences in methylation in patients between high-risk nondysplastic BE, which will progress to cancer, versus low-risk BE
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