Spectrum of <i>TERT</i> promoter mutations and mechanisms of activation in thyroid cancer

Panebianco, Federica; Nikitski, Alyaksandr V.; Nikiforova, Marina N.

doi:10.1002/cam4.2467

Cited by 62 publications

(59 citation statements)

References 43 publications

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“…3a, Additional files 7 and 8: Tables S7 and S8). Matching our TERTp dup with the two cases of TERTp dup previously reported (Additional files 9 and 10: Tables S9 and S10) [21,23], JASPAR predicted that all variants determined an increase of binding sites for 21 common TFs, and confirmed that the Sp/KLF family was the most frequently involved (14/21) (Fig. 3b, Additional file 11: Table S11).…”

Section: In Silico Analysis Predicts Tertp Mut Effectssupporting

confidence: 81%

“…2c, Additional file 7: Table S7). Likewise, an increased number of binding sites or an enhanced affinity for the ETS TFs, has been previously reported in a thyroid cancer harbouring a TERTp c.1-104_1-83dup variant, and in cases bearing TERTp -124 or TERTp -146 mutations [3,10,23]. Bioinformatic analyses were consistent with the luciferase data showing a significant increase of TERT expression in cells transfected with the new TERTp -110-89 variant as well as with the two recurrent TERTp mut .…”

supporting

confidence: 85%

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New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

Pierini

Nardelli

Fernandez

et al. 2020

acta neuropathol commun

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The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C > T, c.1-146 C > T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTp mut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C > T and c.1-146 C > T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C > T and c.1-146 C > T. In silico analysis predicted the formation of 119 and 108 new transcription factor's recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTp dup) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors' binding capacity, which is also typically increased by the two c.1-124 C > T/c.1-146 C > T hotspot TERTp mut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTp dup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.

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Section: In Silico Analysis Predicts Tertp Mut Effectssupporting

confidence: 81%

supporting

confidence: 85%

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

Pierini

Nardelli

Fernandez

et al. 2020

acta neuropathol commun

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“…Even though the series is small, it is possible to report that malignant thyroid tumours are frequently TERT mRNA positive in the absence of hotspot TERT p mutations and the mechanism by which TERT re-expression occurs in these cases remains largely unknown. A recent study reported that in thyroid cancer, the hotspot mutations c.1−124C > T and c.1−146C > T are the most frequently detected mutations, but there are other alterations in the promoter [ 45 ]. Supporting the latter point, one study analysed several TERT genetic alterations, including the TERT p mutations, TERT mRNA expression, TERT p hypermethylation and TERT gene copy number in follicular patterned tumours (FTC, FTA and atypical FTA).…”

Section: Discussionmentioning

confidence: 99%

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

Pestana

Batısta

Celestino

et al. 2020

Cancers

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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.

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“…A recent study by Panebianco et al, of 184 tumors of various thyroid cancer subtypes-PTC, FTC, HCC, MTC, and PDTC/ATC, identified an increased TERT copy number in 4.9% of tumors (65). Specifically, 1/107 (0.9%) PTCs displayed four copies of TERT; while 2/22 (9%) FTCs, 4/29 (13.8%) HCCs, 0/22 (0%) MTCs, and 2/4 (50%) PDTCs/ATCs harbored three copies of TERT.…”

Section: Tert Copy Number Amplificationsmentioning

confidence: 98%

Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

2020

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Telomerase reverse transcriptase (TERT) is the catalytic subunit of the enzyme telomerase and is essential for telomerase activity. Upregulation of TERT expression and resulting telomerase activity occurs in the large majority of malignancies, including thyroid cancer. This upregulation results in continued cellular proliferation and avoidance of cellular senescence and cell death. In this review we will briefly introduce TERT and telomerase activity as it pertains to thyroid cancer and, highlight the effects of TERT on cancer cells. We will also explore in detail the different TERT regulatory strategies and how TERT is reactivated in thyroid cancer cells, specifically. These regulatory mechanisms include both activating single base pair TERT promoter mutations and epigenetic changes at the promoter, including changes in CpG methylation and histone modifications that affect chromatin structure. Further, regulation includes the allele-specific regulation of the TERT promoter in thyroid cancer cells harboring the TERT promoter mutation. These entail allele-specific transcriptional activator binding, DNA methylation, histone modifications, and mono-allelic expression of TERT. Lastly, TERT copy number alterations and alternative splicing are also implicated. Both amplifications of the TERT locus and increased full-length transcripts and decreased inactive and dominant negative isoforms result in active telomerase. Finally, the clinical significance of TERT in thyroid cancer is also reviewed.

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Spectrum of TERT promoter mutations and mechanisms of activation in thyroid cancer

Cited by 62 publications

References 43 publications

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma

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

Telomerase Reverse Transcriptase (TERT) Regulation in Thyroid Cancer: A Review

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