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

Abstract

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.

Keywords: Cancer biomarker; telomerase; telomerase reverse transcriptase promoter mutations (TERT promoter mutations); thyroid carcinoma (TC); thyroid nodule.

Figure 1

TERT promoter mutations/telomerase activation, GABPA/B transcription factors and their relation to TC. (A) TERT promoter mutations/telomerase activation and their transcription activator GABPA-B complex. C>T mutation occurs at one of two positions of the TERT proximal promoter (−124 and −146 to ATG for C228T and C250T, respectively) in TC and other malignant cells. The mutation creates a de novo ETS binding motif, and the ETS family members GABPA and GABPB1 or GABPB2 form a complex that binds to the de novo ETS site, and thereby activates the transcription of the TERT gene. The induced TERT gene together with ubiquitously expressed TERC and other components form an active telomerase complex for telomere lengthening. Of note, the presence of two ETS motifs close to each other is preferably recognized and bound by the GABP complex, and two complexes further form a heterotetramer (GABPA-GABPB)2 for stronger transcriptional activity. N: Native ETS site in the TERT promoter. (B) GABPA depletion robustly promotes the invasiveness of ATC-derived cells harbouring C228T. ATC-derived cells were transfected with scramble control and two different GABPA-specific siRNAs, respectively; these cells were then analyzed for their invasion capacity. (C) The association between GABPA expression and survival and TERT promoter mutations in PTC patients. The analysis included 93 PTC patients and higher GABPA expression predicted longer overall and disease-free survival (left and middle panels). The PTC tumors bearing the mutated TERT promoter expressed significantly lower levels of GABPA (right). (B,C) panels was reproduced from (33) with permission from Springer Nature. TERT, telomerase reverse transcriptase; TC, thyroid carcinoma; ATC, anaplastic thyroid carcinoma; PTC, papillary thyroid carcinoma.

Figure 2

The model for TERT promoter mutations, TERT expression and telomerase activation during the pathogenesis of TC. Oncogenic events target BRAF/RAS for their mutations or RET-PTC/PAX8-PPARγ for their fusion in thyrocytes. These mutations or fusions result in the hyperactivation of the MAPK pathway and drive the thyrocytes to over-proliferate, which in turn leads to premature cell senescence so-called OIS. However, the pituitary gland may secrete increased amounts of TSH, through which TP53 function is inhibited. When this happens, cells bypass senescence or M1 phase and continue to proliferate, causing telomere dysfunction. Shortened telomeres are a key driving-force in triggering TERT promoter mutations and TERT expression. This group of patients with PTC/FTC may undergo M2 crisis and advance to PDTC or ATC or more aggressive PTC/FTC. De novo PDTCs and ATCs are most likely derived from their precursor cells that have undergone M2, and these cells acquire widespread TP53 inactivation and robust upregulation of TERT expression and telomerase activity. However, the majority of PTCs/FTCs lack TERT promoter mutations and many of them do not express TERT, but they have relatively longer telomeres in the tumors, and the disease is indolent. A minority of PTCs/FTCs express TERT mRNA, and a fraction of them undergo M2 crisis and progress. Conceivably, TERT/telomerase-deficient PTCs/FTCs are transformed without experiencing M2 crisis and thus lack significant chromosome aberrations. TERT, telomerase reverse transcriptase; TC, thyroid carcinoma; OIS, oncogene-induced senescence; TSH, thyroid-stimulating hormone; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; ATC, anaplastic thyroid carcinoma.

Figure 3

The mutated TERT promoter as a prognostic marker in patients with PTC. (A) The overall and disease-free survival of 93 PTC patients was compared between their tumors with wild type (wt) and mutated (mt) TERT promoter (TERTp). The presence of mt TERTp predicts significantly shorter overall and disease-free survival. The data were reproduced from (33) with permission from Springer Nature. (B) The survival analysis was performed on the TCGA cohort of PTC patients. The patient data was downloaded from ciBioPortal for Cancer Genomics (www.ciBioPortal.org) in Jan. 2019. The numbers of patients available for overall and disease-free survival analyses were 312 and 300, respectively.