Telomerase and Telomeres Biology in Thyroid Cancer

Abstract

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy

“…These frequencies are comparable to the ones available in the TCGA database (BRAF: 59.7%, RAS: 13% RET: 6.3% TERT: 9.4%) (6). Although reports in the literature show that BRAF and TERT mutations are related to aggressive thyroid tumors (8,9,35,36), no association was found with the recurrence risk in our set of cases. This result may be explained by the inclusion of patients treated exclusively by total thyroidectomy and radioiodine therapy.…”

TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma

“…One of the hallmarks of malignant neoplasms is an evasion of replicative senescence and out-of-control proliferation, leading to immortalization of cancer cells [ 19 ]. The pivotal mechanism underlying this process is the reactivation of telomerase, an enzyme typically not expressed in somatic cells, but activated in about 80–90% of all malignant neoplasms [ 20 ]. Telomerase is a complex protein.…”

“…In TCs, their frequency is considered as intermediate. However, it increases dramatically from microcarcinomas (frequency reported at the level of about 5%) [ 25 ] to aggressive poorly differentiated and anaplastic TCs (48.8% and 41.8%, respectively) [ 20 ]. It seems to be more common in TCs harboring BRAF V600E mutation [ 26 ].…”

Radiogenomic analysis of cervical lymph node metastasis in papillary thyroid carcinoma: A preliminary study

“…Clinically, mutations in the TERT promoter are frequently examined from FNA samples [27]. PTC tumours harbouring TERT mutations showed more frequent regional LNM spread than did PTC tumours with a wild-type TERT promoter [28], and TERT mutations are markers for metastatic behaviour [29].…”