Abstract
BackgroundReactivation of telomerase reverse transcriptase (TERT) is an important event in cancer. Two hotspot mutations in the TERT promoter region, c.‐124C > T (C228T) and c.‐146C > T (C250T), occur in various cancer types including thyroid cancer. They generate de novo binding sites for E‐twenty‐six (ETS) transcription factors causing increased TERT transcription. The aim of this study was to search for novel TERT promoter mutations and additional mechanisms of TERT activation in thyroid cancer.MethodsWe studied 198 papillary thyroid carcinomas (PTCs), 34 follicular thyroid carcinomas (FTCs), 40 Hürthle cell carcinomas (HCCs), 14 poorly differentiated/anaplastic thyroid carcinomas (PDTC/ATC), and 15 medullary thyroid carcinomas (MTCs) for mutations in an −424 bp to +64 bp region of TERT. The luciferase reporter assay was used to functionally characterize the identified alterations. Copy number variations (CNVs) in the TERT region were analyzed using TaqMan copy number assay and validated with fluorescence in situ hybridization (FISH).ResultsWe detected the hotspot c.‐124C > T and c.‐146C > T mutations in 7% PTC, 18% FTC, 25% HCC, and 86% PDTC/ATC. One PTC carried a c.‐124C > A mutation. Furthermore, we identified two novel mutations resulting in the formation of de novo ETS‐binding motifs: c.‐332C > T in one MTC and c.‐104_‐83dup in one PTC. These genetic alterations, as well as other detected mutations, led to a significant increase in TERT promoter activity when assayed using luciferase reporter system. In addition, 5% of thyroid tumors were found to have ≥3 copies of TERT.ConclusionsThis study confirms the increased prevalence of TERT promoter mutations and CNV in advanced thyroid cancers and describes novel functional alterations in the TERT gene promoter, including a point mutation and small duplication. These mutations, as well as TERT copy number alterations, may represent an additional mechanism of TERT activation in thyroid cancer.
Highlights
Human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that, together with an RNA component, maintains chromosomal integrity by telomere elongation.[1,2] Telomerase is expressed in germline and stem cells, but it is normally repressed in postnatal somatic cells.[3]
A significant advance in this area was achieved after the discovery of recurrent TERT promoter mutations first in melanoma[11,16] and subsequently in many other human cancers including thyroid cancer.[14]
No TERT promoter mutations were previously documented in medullary thyroid carcinoma (MTC).[34]
Summary
Human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that, together with an RNA component, maintains chromosomal integrity by telomere elongation.[1,2] Telomerase is expressed in germline and stem cells, but it is normally repressed in postnatal somatic cells.[3]. Thyroid cancer is the most common type of endocrine tumors.[29] The majority of thyroid tumors arise from thyroid follicular cells, comprising well‐differentiated thyroid papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic (undifferentiated) thyroid carcinoma (ATC).[30] Initiation and progression of thyroid cancer occur through gradual accumulation of early and late genetic and epigenetic events, which lead to the activation of the MAPK and PI3K‐AKT signaling pathways.[31,32] Early genetic events in thyroid cancer progression (ie, BRAF mutations) are frequently found in both well‐differentiated thyroid cancer and in PDTC or ATC, they are involved in tumor initiation and in the predisposition of the tumor to dedifferentiation. The aim of this study was to detect novel mechanisms of TERT activation in thyroid cancer by mutational screening of the extended promoter region of TERT and evaluating copy number variations (CNVs) involving the TERT chromosomal locus in different thyroid cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
