Whole genome methylation analysis of non-dysplastic Barretts oesophagus that progresses to invasive cancer

Abstract

ObjectiveTo investigate differences in methylation between patients with non-dysplastic Barretts oesophagus who progress to invasive adenocarcinoma and those that do not.\n\nDesignA whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with non-dysplastic Barretts Oesophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing\n\nResultsIn total, 12 patients with \"progressive\" vs. 12 with \"non-progressive\" non-dysplastic Barretts oesophagus were analysed via methylation array. Fourty-four methylation markers were identified that may be able to discriminate between non-dysplastic Barretts Oesophagus that either progress to adenocarcinoma or remain static. Hypomethylation of the recently identified tumour supressor OR3A4 (probe cg09890332) validated in a separate cohort of samples (median methylation in progressors = 67.8% vs. 96.7% in non-progressors,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 two groups, but a global trend towards hypomethylation in the progressor group was observed.\n\nConclusionHypomethylation of OR3A4 has the ability to risk stratify the patient with non-dysplastic Barretts Oesophagus and may form the basis of a future surveillance program.