TERT Promoter Mutations in Thyroid Cancer

Abstract

Two mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) have recently been described in different types of cancer including follicular cell-derived thyroid cancer (TC). In this paper, we reviewed the rates of these mutations in different types and subtypes of TC, their association with a number of clinical and histopathological features and outcome of TC, and their potential diagnostic and prognostic roles in TC. The overall rate of these mutations in TC is about 14 % with least prevalence in the well-differentiated subtypes of papillary thyroid cancer (10-13 %). Their rates increase significantly with increasing aggressiveness of TC reaching about 40 % in the undifferentiated and anaplastic thyroid cancers. There is also clear association with increasing age of patients at the time of diagnosis of TC. The evidence is compelling but with some conflicting results for associations between TERT promoter mutations and tumor size, extrathyroidal invasion, distant metastases, high tumor TNM stage, BRAF (V600E) mutation, recurrence, and mortality. A couple of studies reported a potential diagnostic role for TERT promoter mutations in thyroid nodules with indeterminate cytology of fine needle aspiration biopsy. These studies showed 100 % specificity but very low sensitivity of 7-10 %. The sensitivity increases significantly when TERT promoter mutation testing is combined with other gene mutations, particularly BRAF (V600E) and RAS mutations. Although TERT promoter mutations seem to play significant roles in the pathogenesis of TC, the mechanisms by which they contribute to carcinogenesis remain elusive and future work is needed to fully assess the roles, interactions, and impact of these mutations on the pathogenesis, diagnosis, prognosis, and therapeutics of TC.

Fig. 1

Total numbers of TERT promoter mutations reported in 15 studies that included 3613 thyroid cancer patients

Fig. 2

Percentages of patients with TERT promoter mutations in different subtypes of TC. CPTC classical papillary thyroid cancer, FVPTC follicular variant papillary thyroid cancer, TCPTC tall cell variant papillary thyroid cancer, FTC follicular thyroid cancer, PDTC poorly differentiated thyroid cancer, ATC anaplastic thyroid cancer

Fig. 3

A meta-analysis for an association between TERT promoter mutations and different clinical, histopathological, and outcome of papillary thyroid cancer showing a significant association with age, tumor size, extrathyroidal tumor extension/invasion, distant metastasis, high tumor stage (III/IV), BRAF ^V600E mutation, persistent/recurrent disease, and cancer-specific mortality. The analysis showed no significant associations between TERT promoter mutations and vascular invasion and lymph node metastasis. The test of heterogeneity is at the left lower corner of each graph. Fixed-effect model was used when I² was <25 % and P value >0.05. In other situations, a random-effect model was used for the meta-analysis