Altered 5-hydroxymethylcytosine landscape in primary gastric adenocarcinoma

Multiple factors, including molecular, genetic, and epigenetic changes, have been linked to gastric cancer formation and progression. Cytosine methylation (5mC) has been well studied and recognized as a critical epigenetic mark in the mammalian genome. The recent novel discovery of 5-hydroxymethylcytosine (5hmC), which generated by ten-eleven translocation (TET) enzymes, provide new perspective to understand DNA methylation-related plasticity. Here we show that gastric tumors display significant loss of 5hmC. Using matched distant normal, peripheral and tumor primary tissues, we performed genome-wide profiling of 5hmC and identified differentially hydroxymethylated regions (DhMRs) specifically associated with gastric tumors. Gene Ontology (GO) analyses indicated that DhMRs (both loss-of-5hmC and gain-of-5hmC) were enriched among the genes involved in specific pathways. Interestingly the binding motif of hypoxia-inducible factor 1 (HIF1) is enriched among both peripheral and tumor DhMRs, while the Myc-binding motif is specifically enriched among only tumor DhMRs. Tumor progression analyses revealed a unique set of DhMRs that correlate with tumor progression. These data together suggest that the alteration of 5hmC could potentially contribute to the tumorigenesis of gastric tumors. To explore the role of 5hmC in GC, we collected six sets of fresh gastric tissues, including gastric tumor (Tumor/T), adjacent gastric tissue to the tumor (Peripheral/P) and distant normal gastric tissue (Normal/N).