Epigenetic Dysregulation in Thyroid Cancer: From Molecular Mechanisms to Precision Oncology

Abstract

: Epigenetic dysregulation has emerged as a critical layer of molecular control in thyroid cancer (TC), complementing classical genetic alterations such as BRAF, RAS, and TERT promoter mutations. Aberrant DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) contribute to thyroid tumorigenesis, progression, dedifferentiation, and therapeutic resistance. The aim of this review was to summarize the current evidence on the role of epigenetic alterations in TC and their potential diagnostic and therapeutic implications. A narrative review of the literature was conducted focusing on the principal epigenetic mechanisms involved in TC, including DNA methylation, histone modifications, chromatin remodeling, and ncRNA-mediated regulation. Particular emphasis was placed on their biological significance, clinical relevance, and emerging therapeutic applications. Epigenetic alterations play a pivotal role in TC initiation and progression. In differentiated thyroid cancer (DTC), epigenetic silencing of thyroid-specific genes, including SLC5A5, TSHR, TG, and TPO, contributes to impaired radioactive iodine (RAI) uptake and the development of RAI-refractory disease. In poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), global hypomethylation, chromosomal instability, altered histone modifications, and deregulated non-coding RNA networks contribute to aggressive tumor behavior and intratumoral heterogeneity. Epigenetic biomarkers, including DNA methylation signatures and circulating microRNAs, may improve diagnosis, prognostic stratification, and prediction of treatment response. Preclinical and early clinical studies also support the potential of epigenetic therapies, particularly in combination with targeted agents, to restore thyroid differentiation and overcome therapeutic resistance. Epigenetic alterations represent promising biomarkers and therapeutic targets in TC. Although encouraging advances have been achieved, further translational research and prospective clinical studies are required to validate epigenetic biomarkers and optimize epigenetic-based therapeutic strategies before their routine implementation in precision oncology for advanced and RAI-refractory TC.