Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

Abstract

Telomerase reverse transcriptase (TERT) is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation of TERT expression and resulting telomerase activity occurs in the large majority of malignancies, including thyroid cancer. This upregulation results in continued cellular proliferation and avoidance of cellular senescence and cell death. In this review we will briefly introduce TERT and telomerase activity as it pertains to thyroid cancer and, highlight the effects of TERT on cancer cells. We will also explore in detail the different TERT regulatory strategies and how TERT is reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pair TERT promoter mutations and epigenetic changes at the promoter, including changes in CpG methylation and histone modifications that affect chromatin structure. Further, regulation includes the allele-specific regulation of the TERT promoter in thyroid cancer cells harboring the TERT promoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression of TERT. Lastly, TERT copy number alterations and alternative splicing are also implicated. Both amplifications of the TERT locus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance of TERT in thyroid cancer is also reviewed.

Characterization of TERT and BRAF copy number variation in papillary thyroid carcinoma: An analysis of the cancer genome atlas study

“…TERT alterations may lead to activation of telomerase 15 . The prevalence of both TERT mutations and TERT amplification increases in advanced stages of disease, 15 and both TERT mutations, and TERT amplification are associated with increased TERT expression 16 .…”

“…TERT alterations may lead to activation of telomerase 15 . The prevalence of both TERT mutations and TERT amplification increases in advanced stages of disease, 15 and both TERT mutations, and TERT amplification are associated with increased TERT expression 16 . We also found that PTCs with a TERT promoter mutation were more likely to have a TERT amplification (13%) than wildtype TERT tumors (3.2%, Figure 3), and tumors harboring both TERT alterations had the highest levels TERT expression, suggesting that the two TERT alterations may work in concert.…”

Proposal of a New Prognostic Model for Differentiated Thyroid Cancer with TERT Promoter Mutations

“…However, there are some problems. Approximately 30% of DTC patients are downstaged to stage I or II, so there are too few patients with stage III and IV disease [6,9], and there is no molecular profile of clinical prognostic significance that has recently emerged [10,11]. In addition, a large multicenter cohort study showed the poor predictability of TNM-8 in the CSS of follicular thyroid cancer (FTC) patients [12].…”

Utility of droplet digital polymerase chain reaction for TERT and BRAF mutational profiling of thyroid nodules

“…TERT expression can be upregulated through several mechanisms including promoter mutations, TERT gene copy number alterations, increased promoter methylation and histone modifications [ 14 – 18 ]. These TERT-related genetic aberrations have been implicated in thyroid cancer with particular prevalence in aggressive subtypes [ 15 , 16 ]. They have a high specificity and positive predictive value for thyroid cancer [ 19 ] and have been associated with poorer patient outcomes, including a greater risk of death [ 14 , 15 , 20 ].…”