TERT promoter mutations in thyroid cancer

Abstract

The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.

Keywords: BRAF V600E mutation; TERT promoter mutation; diagnosis; genetic molecular markers; prognosis; telomerase reverse transcriptase; thyroid cancer.

Figure 1

Meta-analysis of the association of TERT promoter mutations with extrathyroidal invasion (A) and vascular invasion (B) of thyroid cancer. The between-study heterogeneity was tested by a Chi-square-based Q-test and quantified by the I² metric, which ranged from 0 to 100 % and was considered low for I²<25%, modest for 25–50%, and large for >50% (Higgins, et al. 2003). The combined OR was calculated by the fixed-effects model (the Mantel-Haenszel method) when between-study heterogeneity was absent (Mantel & Haenszel,1959); otherwise the random-effects model (the Dersimonian and Laird method) was used (Dersimonian & Laird, 1986). The circles and horizontal lines correspond to the study-specific OR and 95% CI, respectively. The combined ORs and their 95% CIs are indicated by the diamonds. PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer. OR, odds ratio; 95% CI, 95% confidence interval.

Figure 2

Meta-analysis of the association of TERT promoter mutations with thyroid cancer distant metastasis (A), tumor stage III/IV (B), tumor recurrence (C), and patients mortality (D). The between-study heterogeneity and combined OR were calculated as described in the legend to Figure 1. The circles and horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI). The combined ORs and their 95% CIs are indicated by the diamonds. PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer. OR, odds ratio; 95% CI, 95% confidence interval.

Figure 3

Meta-analysis of the association between BRAF V600E and TERT promoter mutations in thyroid cancer. The between-study heterogeneity and combined OR were calculated as described in Figure 1. The circles and horizontal lines correspond to the study-specific odds ratio (OR) and 95% confidence interval (CI). The combined ORs and their 95% CIs are indicated by the diamonds. PTC, papillary thyroid cancer; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid cancer. OR, odds ratio; 95% CI, 95% confidence interval.