scholarly journals Telomerase and Telomeres Biology in Thyroid Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2887 ◽  
Author(s):  
Benedetta Donati ◽  
Alessia Ciarrocchi
Keyword(s):  
Current Knowledge ◽  
Telomerase Activity ◽  
High Rate ◽  
Cancer Therapies ◽  
Telomerase Inhibitors ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Regulation ◽  
Promoter Mutations

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.

scholarly journals Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

2019 ◽  
Vol 20 (6) ◽  
pp. 1333 ◽  
Author(s):  
Alessandra Ventura ◽  
Cristina Pellegrini ◽  
Ludovica Cardelli ◽  
Tea Rocco ◽  
Valeria Ciciarelli ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Telomerase Activity ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Biology ◽  
Promoter Mutations

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

scholarly journals The role of telomerase reverse transcriptase (TERT) promoter mutations in prognosis in bladder cancer

Bioengineered ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 1495-1504
Author(s):  
Song Wan ◽  
Xuan Liu ◽  
Wei Hua ◽  
Ming Xi ◽  
Yulin Zhou ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Reverse Transcriptase ◽  
Telomerase Reverse Transcriptase ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals Cancer-associated TERT promoter mutations abrogate telomerase silencing

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Kunitoshi Chiba ◽  
Joshua Z Johnson ◽  
Jacob M Vogan ◽  
Tina Wagner ◽  
John M Boyle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem ◽  
Telomerase Activity ◽  
Human Telomerase Reverse Transcriptase ◽  
Telomere Shortening ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Human Telomerase ◽  
Promoter Mutations ◽  
Additional Tumor

Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.

scholarly journals Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis

2018 ◽  
Vol 15 (6) ◽  
pp. 386-393 ◽  
Author(s):  
Cagatay Günes ◽  
Felix Wezel ◽  
Jennifer Southgate ◽  
Christian Bolenz
Keyword(s):  
Telomerase Activity ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

scholarly journals TERT Promoter Mutation is a Diagnostic and Differential Diagnostic Marker for Tumors with Urothelial Origin

2020 ◽  
Vol 4 (2) ◽  
Author(s):  
Shaobo Zhang
Keyword(s):  
Differential Diagnosis ◽  
Diagnostic Marker ◽  
Clinical Implications ◽  
Telomerase Reverse Transcriptase ◽  
Tert Promoter Mutation ◽  
Promoter Mutation ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Telomerase reverse transcriptase (TERT) promoter mutations have been found in approximately 60–80% of bladder urothelial cancers and its variants of all grades anywhere in the urinary tract. The TERT promoter mutations occur early in urothelial neoplasia and are biomarkers for neoplasm development, recurrence, diagnosis, differential diagnosis, and potentially a therapeutic target. This review highlighted the role of TERT promoter mutations in urothelial tumorigenesis, and the potential clinical implications.

scholarly journals Role of molecular markers to predict distant metastasis in papillary thyroid carcinoma: Promising value of TERT promoter mutations and insignificant role of BRAF mutations—a meta-analysis

Tumor Biology ◽  
2017 ◽  
Vol 39 (10) ◽  
pp. 101042831771391 ◽  
Author(s):  
Huy Gia Vuong ◽  
Ahmed MA Altibi ◽  
Uyen NP Duong ◽  
Hanh TT Ngo ◽  
Thong Quang Pham ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Distant Metastasis ◽  
Odds Ratio ◽  
Meta Analysis ◽  
Papillary Thyroid ◽  
Braf Mutations ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

The presence of distant metastasis is associated with an adverse outcome in papillary thyroid cancer. We performed a meta-analysis to investigate the role of molecular markers as predictors for distant metastasis in papillary thyroid cancer. Four electronic databases including PubMed, Web of Science, Scopus, and Virtual Health Library were searched, and odds ratio and its 95% confidence interval concerning the association of BRAF, RAS, and TERT promoter mutations and RET/PTC rearrangements with distant metastasis were calculated using random-effects model. In total, 42 studies with 11,109 papillary thyroid cancers were included for meta-analyses. Overall, the presence of TERT promoter (odds ratio = 5.95; 95% confidence interval = 2.95–11.99), RAS mutations (odds ratio = 2.5; 95% confidence interval = 1.00–6.22), and RET/PTC rearrangements (odds ratio = 1.92; 95% confidence interval = 1.03–3.56) were found to be associated with a significantly increased risk for distant metastasis. BRAF mutations were not associated with an elevated risk for distant metastasis (odds ratio = 0.79; 95% confidence interval = 0.54–1.16). In conclusion, our study demonstrated the promising value of few molecular biomarkers, especially TERT promoter mutations in predicting distant metastasis in papillary thyroid cancers, while BRAF mutations showed no association with distant metastasis. Our study affirms the value of selected mutations for tumor risk stratification and assessment of patients’ prognosis.

scholarly journals Frequent Somatic TERT Promoter Mutations in Thyroid Cancer: Higher Prevalence in Advanced Forms of the Disease

2013 ◽  
Vol 98 (9) ◽  
pp. E1562-E1566 ◽  
Author(s):  
Iñigo Landa ◽  
Ian Ganly ◽  
Timothy A. Chan ◽  
Norisato Mitsutake ◽  
Michiko Matsuse ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Transcriptional Response ◽  
Telomerase Activity ◽  
Wild Type ◽  
Thyroid Cancers ◽  
Ras Mutations ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Background: TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas. Objectives: The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC. Methods: TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs). Results: TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P = 3 × 10−4 vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10−4), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04). Conclusions: TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression.

scholarly journals TERT, a promoter of CNS malignancies

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Bhuvic Patel ◽  
Rukayat Taiwo ◽  
Albert H Kim ◽  
Gavin P Dunn
Keyword(s):  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Promoter Hypermethylation ◽  
Telomerase Activity ◽  
Cns Tumors ◽  
Replication Process ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Biology ◽  
Promoter Mutations

Abstract As cells replicate their DNA during mitosis, telomeres are shortened due to the inherent limitations of the DNA replication process. Maintenance of telomere length is critical for cancer cells to overcome cellular senescence induced by telomere shortening. Telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of telomerase, an RNA-dependent DNA polymerase that lengthens telomeric DNA to maintain telomere homeostasis. TERT promoter mutations, which result in the upregulation of TERT transcription, have been identified in several central nervous system (CNS) tumors, including meningiomas, medulloblastomas, and primary glial neoplasms. Furthermore, TERT promoter hypermethylation, which also results in increased TERT transcription, has been observed in ependymomas and pediatric brain tumors. The high frequency of TERT dysregulation observed in a variety of high-grade cancers makes telomerase activity an attractive target for developing novel therapeutics. In this review, we briefly discuss normal telomere biology, as well as the structure, function, and regulation of TERT in normal human cells. We also highlight the role of TERT in cancer biology, focusing on primary CNS tumors. Finally, we summarize the clinical significance of TERT promoter mutations in cancer, the molecular mechanisms through which these mutations promote oncogenesis, and recent advances in cancer therapies targeting TERT.

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