TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas

Melo, Miguel; Rocha, Adriana Gaspar da; Vinagre, João; Batısta, Rui; Peixoto, Joana; Tavares, Catarina; Celestino, Ricardo; Almeida, Ana Paula de; Salgado, Catarina; Eloy, Catarina; Castro, Patrícia; Prazeres, Hugo; Lima, Jorge; Amaro, Teresina; Lobo, Cláudia; Martins, Maria João; Moura, M. M.; Cavaco, Branca; Leite, Valeriano; Cameselle-Teijeiro, José; Carrilho, Francisco; Carvalheiro, Manuela; Máximo, Valdemar; Sobrinho-Simões, Manuel; Soares, Paula

doi:10.1210/jc.2013-3734

Cited by 460 publications

(505 citation statements)

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“…In primary glioblastomas, 20 differentiated thyroid carcinomas 30 and urothelial carcinomas of the urinary bladder, 28 TERT promoter mutation was an indicator of poor clinical outcome. In ovarian clear cell carcinomas, Widschwendter et al 15 and Wu et al 21 reported that TERT expression and TERT promoter mutation revealed no prognostic impact.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…In glioblastomas and papillary thyroid cancer, the mutations were associated with older age at diagnosis [3]. Another recent study demonstrated association Mixed tumor 9 − SX I n/a n/a n/a Alive 4 c.-146:C>T TT 43 Seminoma 6.5 + S1 I n/a n/a n/a Alive n/a not applicable a Vascular invasion between TERT promoter mutations and older patient age, larger tumor size, distant metastases, and shorter disease specific survival in papillary thyroid cancer [23]. In melanoma, TERT promoter mutations were also associated with shorter disease free survival [24].…”

Section: Discussionmentioning

confidence: 99%

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

et al. 2015

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The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.-146:C>T, were recently identified in a range of human cancers and have been associated with a more aggressive behavior. Testicular germ cell tumors frequently exhibit a good prognosis; however, the development of refractory disease is still a clinical challenge. In this study, we aim to evaluate for the first time the presence of the hotspot telomerase reverse transcriptase gene promoter mutations in testicular germ cell tumors. A series of 150 testicular germ cell tumor cases and four germ cell tumor cell lines were evaluated by PCR followed by direct Sanger sequencing and correlated with patient's clinical pathological features. Additionally, we genotyped the telomerase reverse transcriptase gene promoter single nucleotide polymorphism rs2853669 (T>C) located at −245 position. We observed the presence of the TERT promoter mutation in four patients, one exhibited the c.-124:C>T and three the c.-146:C>T. No association between TERT mutation status and clinicopathological features could be identified. The analysis of the rs2853669 showed that variant C was present in 22.8 % of the cases. In conclusion, we showed for the first time that TERT promoter mutations occur in a small subset (~3 %) of testicular germ cell tumors.

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“…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: 97%

“…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%

“…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]. 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).…”

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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TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas

Cited by 460 publications

References 41 publications

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

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

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

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