Altered DNA modifications in Barrett's oesophagus and oesophageal adenocarcinoma

Cytosine in human DNA can be modified by DNA methyltransferases (DNMTs) and the Ten-Eleven Translocation (TET) family of oxygenases. Activity of these enzymes results in four modifications, among which 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are the major ones. Different patterns of localisation of both these modifications relate to gene transcription and the developmental origin of different cell types. Cancers have been shown to have globally altered DNA modifications, however it is poorly understood when in carcinogenesis the shift in DNA modifications happens and how it influences tumour growth. Here we mapped 5mC and 5hmC genome-wide at single nucleotide resolution in Barrett’s oesophagus, a well-known pre-malignant precursor of oesophageal adenocarcinoma (OAC). To get better insight into alterations in Barrett’s oesophagus (BO), we also analysed samples from OAC, adjacent normal oesophagus and gastric and duodenal epithelia. We found substantial global hypomethylation outside genic regions in Barrett’s oesophagus. Specific hypermethylation was evident in gene regulatory regions as defined by DNAseI hypersensitive sites. Moreover, we observed elevated methylation at CpG islands in a fraction of genes, which have reduced expression in Barrett’s oesophagus. While we find 5hmC depleted both in BO and OAC, distribution of the modification in CpG islands is different. Overall our results demonstrate that cancer-specific epigenetic alterations can already be found in benign Barrett’s oesophagus, suggesting early redistribution of DNA modifications in the process of transformation. Citation Format: Skirmantas Kriaucionis, Marketa Tomova, Sophie Kirschner, Pijus Brazauskas, Mankgopo Kgatle, Richard Owen, Michael White, Benjamin Schuster-Boeckler, Xin Lu. Altered DNA modifications in Barrett’s oesophagus and oesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 835.