Epigenetic Dysregulation in Thyroid Neoplasia Tetsuo Kondo, MD, PhD a , Sylvia L. Asa, MD, PhD b,c , Shereen Ezzat, MD b,d, * a Department of Pathology, University of Yamanashi, Japan b Ontario Cancer Institute, University Health Network, 610 University Avenue #8-327, Toronto, ON, M5P 2S3, Canada c Department of Pathology and Laboratory Medicine, University of Toronto, Toronto, ON, Canada d Department of Medicine, University of Toronto, Toronto, ON, Canada Gain-of-function mutations in oncogenes, including RET, RAS, and BRAF, have greatly aided our understanding of the molecular mechanisms of thyroid carcinogenesis [1]. It is also clear that mutations or deletions cause inactivation of tumor suppressor genes such as p53/TP53 in thyroid carcinomas [1]. However, recent advances have further disclosed the signif- icance of epigenetic events in the development and progression of human tumorigenesis [2]. Indeed, various tumor-suppressor genes and thyroid hor- mone–related genes are epigenetically silenced in thyroid tumors [3]. The epigenetic pattern of gene silencing is also associated with certain histologic types of thyroid tumors. This article reviews the evidence for epigenetic gene dysregulation in follicular cell–derived thyroid carcinomas including papil- lary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and un- differentiated thyroid carcinoma (UTC). We also discuss future applications of epigenetics as ancillary diagnostic tools and in the design of targeted ther- apies for thyroid cancer. Epigenetic gene regulation Epigenetic modification is responsible for regulation of gene expression by mammalian cells without involving changes in the underlying genomic DNA sequence (Fig. 1). The mechanisms include methylation of cytosine * Corresponding author. Ontario Cancer Institute, 610 University Avenue #8-327, Toronto, ON, M5P 2S3, Canada. E-mail address: shereen.ezzat@utoronto.ca (S. Ezzat). 0889-8529/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2007.12.002 endo.theclinics.com Endocrinol Metab Clin N Am 37 (2008) 389–400