TERT reactivation in thyroid cancer: mechanisms, clinical implications, and therapeutic opportunities
Year: 2026
Type: article
Abstract: Somatic mutations in the telomerase reverse transcriptase (TERT) promoter are key molecular events in thyroid carcinogenesis and are strongly associated with aggressive clinical behaviour. The c.-124C>T and c.-146C>T hotspot mutations, discovered in 2013, are now recognised as major mechanisms of TERT reactivation and as independent predictors of disease-specific survival, recurrence, and disease refractoriness to radioiodine. TERT can also be reactivated by multiple regulatory layers converging on telomerase upregulation. Beyond telomere maintenance, TERT enhances ribosome biogenesis, cooperates with BRAFV600E-driven transcriptional programmes, and modulates NF-κB-associated inflammatory and stress responses, thereby promoting dedifferentiation and therapy resistance. Clinically, TERT promoter mutations, particularly when co-occurring with BRAFV600E, increase in prevalence from papillary to anaplastic thyroid carcinoma and are associated with an increased risk of radioiodine-refractory disease, supporting their use in risk stratification. However, isolated TERT promoter mutations are more often associated with intermediate risk tumours and comparatively better outcomes, underscoring the importance of molecular context. The recent approval of the telomerase inhibitor imetelstat and the preclinical success of the rRNA transcription inhibitor CX5461 in restoring differentiation and iodine uptake support telomerase- and ribosome-targeted strategies as emerging therapeutic avenues for TERT-driven thyroid cancers.
Source: European Thyroid Journal
DOI: 10.1530/etj-26-0068
Authors: Linh T T Nguyen, Anthony Glover, Matti Gild, Martyn Bullock
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7212027389