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

By MP Dilworth, T Nieto, JD Stockton, C Whalley, L. Tee, JD James, MT Hallissey, R Hejmadi, N Trugdill, O Tucker, AD Beggs

Posted 06 Mar 2017
bioRxiv DOI: 10.1101/114298

Objective: To investigate differences in methylation between patients with non-dysplastic Barrett's oesophagus who progress to invasive adenocarcinoma and those that do not. Design: A whole genome methylation interrogation using the Illumina HumanMethylation 450 array of patients with non-dysplastic Barrett's Oesophagus who either develop adenocarcinoma or remain static, with validation of findings by bisulfite pyrosequencing. Results: In total, 12 patients with “progressive” vs. 12 with “non-progressive” non-dysplastic Barrett's oesophagus were analysed via methylation array. Fourty-four methylation markers were identified that may be able to discriminate between non-dysplastic Barrett's 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. Conclusion: Hypomethylation of OR3A4 has the ability to risk stratify the patient with non-dysplastic Barrett's Oesophagus and may form the basis of a future surveillance program.

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