The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas

Liu, T; Wang, N; Cao, Jing; Sofiadis, Anastasios; Dinets, Andrii; Zedenius, Jan; Larsson, Catharina; Xu, Dawei

doi:10.1038/onc.2013.446

Cited by 217 publications

(315 citation statements)

References 28 publications

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“…In a large series of 469 follicular cell-derived thyroid carcinomas (FCDTC), TERT promoter mutations were found in 7.5 % of PTC, 17.1 % of FTC, 29.0 % of poorly differentiated thyroid carcinomas (PDTC) and 33.0 % of anaplastic thyroid carcinomas (ATC) [80]. This stepwise increase in the frequency of TERT promoter mutations from well to poorly differentiated and undifferentiated carcinomas was also reported in other studies [66,74] (Table 2). TERT promoter mutations were not detected in normal thyroid tissue, benign lesions or medullary thyroid carcinoma (MTC).…”

Section: Telomerase Promoter Mutations In Thyroid Carcinomassupporting

confidence: 76%

“…The majority (about 80 %) of mutated cases presented the −124G>A mutation. In PTC, TERT promoter mutations were significantly more frequent in BRAF-mutated tumours than in BRAF wild-type tumours [74,75,80,121]. The TERT promoter mutations were associated with increased mRNA expression, and this increase was particularly pronounced in tumours harbouring both BRAF and TERT promoter mutations [121].…”

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 96%

“…In summary, the aforementioned findings suggest that telomerase activity may be associated with a more aggressive clinical behaviour of thyroid tumours. Recently, somatic mutations in the promoter region of TERT were reported in thyroid tumours [66,74,75,121]. In a large series of 469 follicular cell-derived thyroid carcinomas (FCDTC), TERT promoter mutations were found in 7.5 % of PTC, 17.1 % of FTC, 29.0 % of poorly differentiated thyroid carcinomas (PDTC) and 33.0 % of anaplastic thyroid carcinomas (ATC) [80].…”

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 99%

“…Two studies analysed the relationship between TERT promoter mutations, clinico-pathological features and outcome. TERT promoter mutations were significantly associated with older age at diagnosis [74,80], larger tumour size and higher stage [80]. TERT promoter mutations were also found to be an independent predictor of distant metastases and disease persistence at the end of follow-up in differentiated thyroid carcinomas (DTC) [80].…”

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 99%

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Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

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Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the "alternative mechanism of telomere lengthening" (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and nonneoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.

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Section: Telomerase Promoter Mutations In Thyroid Carcinomassupporting

confidence: 76%

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 96%

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 99%

Section: Telomerase Promoter Mutations In Thyroid Carcinomasmentioning

confidence: 99%

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Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

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“…The correlation between TERT promoter mutations and older patient age has been shown in glioblastoma, medulloblastoma, 20 papillary thyroid carcinoma (445 years old), 27 and urothelial carcinoma of the urinary bladder (450 years old). 28 In contrast, a previous study by Wu et al showed that no relationship could be found between patient age and TERT promoter mutations.…”

Section: Discussionmentioning

confidence: 97%

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (Po0.001), preserved ARID1A immunoreactivity (P ¼ 0.017) and infrequent PIK3CA mutation (P ¼ 0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age 445 (P ¼ 0.045) and preserved ARID1A expression (P ¼ 0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P ¼ 0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P ¼ 0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy. Modern Pathology (2015) 28, 303-311; doi:10.1038/modpathol.2014 published online 1 August 2014 Ovarian clear cell carcinoma represents 5-25% of all epithelial ovarian carcinomas with geographic variation. 1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy.

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Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan‐cancer analysis

et al. 2022

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Telomerase activation is required for malignant transformation. Recent advances in high‐throughput technologies have enabled the generation of complex datasets, thus providing alternative approaches to exploring telomerase biology more comprehensively, which has proven to be challenging due to the need for laborious assays required to test for telomerase activity. To solve these issues, several groups have analyzed TCGA pan‐cancer tumor datasets by investigating telomerase reverse transcriptase (TERT), the catalytic subunit for telomerase activity, or its surrogates. However, telomerase is a multiunit complex containing not only TERT, but also numerus cofactors required for telomerase function. Here we determined genomic and molecular alterations of 10 well‐characterized telomerase components in the TCGA and CCLE datasets. We calculated a telomerase score (TS) based on their expression profiles and clustered tumors into low, high, and intermediate subtypes. To validate the in silico analysis result, we used immunoblotting and telomerase assays. High TS subtypes were significantly associated with stemness, proliferation, epithelial to mesenchymal transition, hyperactivation of oncogenic signaling pathways, shorter patient survival, and infiltration of dysfunctional T‐cells or poor response to immunotherapy. Copy number alterations in 10 telomerase components were widespread and associated with the level of their expression. Surprisingly, primary tumors and cancer cell lines frequently displayed a homozygous deletion of the TCAB1 gene, encoding a telomerase protein essential for telomerase trafficking, assembling, and function, as previously reported. However, tumors or cells carrying a TCAB1 deletion still exhibited telomerase activity comparable to or even higher than their wildtype counterparts. Collectively, applying telomerase component‐based TS in complex datasets provided a robust tool for telomerase analyses. Our findings also reveal a tight connection between telomerase and other oncogenic signaling pathways; TCAB1 may acts as a dispensable telomerase component. Moreover, TS may serve as a useful biomarker to predict patient outcomes and response to immunotherapy.

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The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas

Cited by 217 publications

References 28 publications

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan‐cancer analysis

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