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

Authors

Arti Bhan, Henry Ford HealthFollow
M S. Mosella, Henry Ford Health
Michael C. Singer, Henry Ford HealthFollow
Christian Keller, Henry Ford HealthFollow
Rand Abou Shaar, Henry Ford HealthFollow
Steven S. Chang, Henry Ford HealthFollow
Vivian Wu, Henry Ford HealthFollow
J Stephen, Henry Ford Health
Maria J. Worsham, Henry Ford HealthFollow
Laila M. Poisson, Henry Ford HealthFollow
Wamidh L. Alkhoory, Henry Ford HealthFollow
T Malta, Henry Ford Health
Thais S. Sabedot, Henry Ford HealthFollow
Houtan Noushmehr, Henry Ford HealthFollow
Ana V. Castro, Henry Ford HealthFollow

Recommended Citation

Bhan A, Mosella MS, Singer M, Keller CE, Abou Shaar R, Chang S, Wu V, Stephen J, Worsham M, Poisson LM, Alkhoory WL, Malta TM, Sabedot TS, Noushmehr H, and Castro A. DNA methylation signature associated with risk of recurrence in papillary thyroid carcinoma. Thyroid 2018; 28:A24.

Document Type

Conference Proceeding

Publication Date

2018

Publication Title

Thyroid

Abstract

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 < 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.

Volume

28

First Page

A24