Telomerase reverse transcriptase promoter mutations in thyroid carcinomas: implications in precision oncology-a...

Telomerase is a ribonucleoprotein enzyme with telomerase reverse transcriptase (TERT) as a catalytic component. In normal human follicular thyroid cells or thyrocytes, telomerase is silent due to the TERT gene being tightly repressed. However, during the formation of thyroid carcinoma (TC), telomerase becomes activated via TERT induction. The TERT promoter's gain-of-function mutation has recently been identified in TCs and many other malignancies. The mutation creates a de novo ETS-binding motif through which TERT transcription is de-repressed and telomerase is activated; through this, the mutant TERT promoter promotes the development of TC, contributes to disease aggressiveness and treatment resistance, and thereby leads to poor patient outcomes. From a clinical point of view, the strong association between the TERT promoter mutation and disease malignancy and aggressiveness holds great promise for its value in TC diagnostics, risk stratification, prognostication, treatment decision, and follow-up design. In the present review article, we summarize the recent findings of studies of TERT promoter mutations in TC and underscore the implications of TERT hyperactivity driven by genetic events in the pathogenesis and management of TC. Finally, the targeting of TERT promoter mutations and the disruption of telomere maintenance are considered as potential therapeutic strategies against TC.