Comprehensive Assessment of TERT mRNA Expression across a Large Cohort of Benign and Malignant Thyroid Tumours.

Ricardo Celestino,Paula Soares,Ana Pestana,Rui Batista,Manuel Sobrinho-Simões,Sule Canberk

doi:10.3390/cancers12071846

Abstract

The presence of TERT promoter (TERTp) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. TERT mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, TERT mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. TERTp mutations and TERT mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas TERT mRNA expression in the benign tumours is associated with the presence of thyroiditis.

Highlights

Achieving unlimited proliferative potential, cell immortalization, has been considered one of the cancer hallmarks [1]
TERC is widely expressed in several tissues, even in telomerase negative, telomerase reverse transcriptase (TERT) expression is highly regulated, and a positive correlation between TERT mRNA expression and telomerase activity has been reported, suggesting that TERT is the main regulator of telomerase [7,8,9]
TERT promoter (TERTp) Mutations Are Only Found in Malignant Thyroid Tumours

Summary

Introduction

Cell immortalization, has been considered one of the cancer hallmarks [1]. Suggesting that this is a favoured mechanism in cancer cells to circumvent the proliferative barrier [1]. Telomerase is composed of several subunits, it has been shown that two of them are essential for telomerase catalytic activity, the telomerase reverse transcriptase (TERT), the catalytic subunit, and a RNA component (TERC) that provides a template for telomere elongation [4,5,6]. TERC is widely expressed in several tissues, even in telomerase negative, TERT expression is highly regulated, and a positive correlation between TERT mRNA expression and telomerase activity has been reported, suggesting that TERT is the main regulator of telomerase [7,8,9]. TERT promoter (TERTp) mutations have been identified as one of the mechanisms responsible for telomerase re-expression in cancer, being described for the first time in melanoma [10,11]. The TERTp mutations c.1–124 (C228T) and c.1–146 (C250T) residues (C > T or G > A in the reverse strand) [10,11], create an 11-base nucleotide stretch 5’-CCCCTTCCGGGG-3’ which contains a consensus binding site, GGAA (in reverse complement), for E-Twenty Six (ETS) family of transcription factors, providing a basis to the biological relevance of these mutations [10,11]

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