DNA methylation signature associated with risk of recurrence in papillary thyroid carcinoma

The incidence of papillary thyroid carcinoma (PTC) is increasing globally. While the majority of patients with PTCs have an excellent prognosis, select patients present with more aggressive disease. These cases of PTC are associated with genomic alterations. However, little is known about the role of DNA methylation abnormalities in these PTCs. In order to address this, we profiled the DNA methylome of 20 formalin-fixed paraffin-embedded PTCs comprised of high (HR) (stage IV) (n = 14) and low risk (stages I/II) (LR) (n = 6) disease. Supervised analysis was performed between the groups, followed by gene ontology (GO) and motif analyses of probe-related genes/regions. In relation to the LR group, the HR PTCs presented 246 differentially methylated CpG probes (DMPs) (118 hypermethylated and 128 hypomethylated), distributed across CpG islands (CGI) (n = 21, 9%), shores (Sh) (n = 52, 21%) and intergenic/open sea regions (OpS) (n = 173, 70%). The nearest genes associated with the hypermethylated CGI/Sh DMPs were enriched for pathways related to response to stress, brain development and Rap-1 signaling, involved in metastasis of several cancers, while hypomethylated Sh/OpS genes were enriched for amine response and IL-12 signaling pathways. DMP located in the OpS regions overlapped with 151 predicted enhancers, known to be active. Hypomethylated enhancers were enriched for bZIP motifs, binding sites for AP-1 complex-Fra1, Fra2, Fosl2, JunB (p \u3c 0.0001), which have been shown to be involved in tumorigenesis/progression in cancer. Our results suggest that distinct DNA methylation patterns in promoter and non-promoter regions are associated with genes/pathways involved in cell migration and invasion and cancer growth (e.g. Rap-1, AP-1) and novel pathways. These results bolster the hypothesis that DNA methylation participate in the regulatory control of PTC aggressiveness. Further validation of these findings may also offer opportunities to develop drugs targeting PTC growth and recurrence