Retroelements in thyroid cancer: epigenetic plasticity, dedifferentiation, and therapeutic opportunities.

Thyroid tumors display remarkable phenotypic plasticity, particularly in their progression from well-differentiated forms to aggressive, dedifferentiated subtypes such as anaplastic thyroid carcinoma. While genetic drivers such as BRAF, TP53, and members of the RAS gene family underpin key oncogenic transitions, they do not fully explain the profound transcriptional deregulation and therapeutic resistance that characterize advanced disease. Mobile genetic elements, including LINE-1 retrotransposons and human endogenous retroviruses, constitute nearly half of the human genome and normally contribute to gene regulation, chromatin organization and developmental plasticity. However, epigenetic erosion and loss of genome surveillance lead to their aberrant reactivation, generating non-canonical transcripts, regulatory rewiring and insertional mutagenesis. In cancer, TERT promoter mutations have been linked to transcriptional activation of specific endogenous retroviral elements, and TP53 dysfunction exacerbates LINE-1 derepression, functionally connecting classical genetic alterations to mobilome reactivation, genome instability and phenotypic dedifferentiation. Emerging data also indicate that reverse transcriptase inhibitors (e.g., lamivudine, nevirapine) can partially suppress retroelement activity, induce transcriptional reprogramming and restore radioiodine uptake in refractory thyroid tumors, highlighting a potential therapeutic vulnerability. By integrating cancer epigenetics and mobilome biology, this review reframes thyroid tumor evolution as a process shaped not only by genetic alterations but also by retroelement-mediated disruption of genome regulation. Retroelements may serve as biomarkers of aggressive transformation and as actionable targets in translational oncology.