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TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas

2014-05Journal article Open access
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dc.contributor.authorMelo, Miguel
dc.contributor.authorGaspar Da Rocha, Adriana
dc.contributor.authorVinagre, João
dc.contributor.authorBatista, Rui
dc.contributor.authorPeixoto, Joana
dc.contributor.authorTavares, Catarina
dc.contributor.authorCelestino, Ricardo
dc.contributor.authorAlmeida, Ana
dc.contributor.authorSalgado, Catarina
dc.contributor.authorEloy, Catarina
dc.contributor.authorCastro, Patrícia
dc.contributor.authorPrazeres, Hugo
dc.contributor.authorLima, Jorge
dc.contributor.authorAmaro, Teresina
dc.contributor.authorLobo, Cláudia
dc.contributor.authorMartins, Maria João
dc.contributor.authorMoura, Margarida
dc.contributor.authorCavaco, Branca
dc.contributor.authorLeite, Valeriano
dc.contributor.authorCameselle-Teijeiro, José
dc.contributor.authorCarrilho, Francisco
dc.contributor.authorCarvalheiro, Manuela
dc.contributor.authorMaximo, Valdemar
dc.contributor.authorSobrinho-Simões, Manuel
dc.contributor.authorSoares, Paula
dc.date.accessioned2015-01-13T11:38:41Z
dc.date.available2015-01-13T11:38:41Z
dc.date.issued2014-05
dc.description.abstractContext: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.por
dc.description.sponsorshipWe acknowledge GENZYME for funding our work through a research project. This study was supported by the Portuguese Foundation for Science and Technology through PhD Grant SFRH/BD/81940/2011 (to J.V.); PhD Grant SFRH/BD/87887/2012 (to C.T.); PhD Grant SFRH/BD/79135/2011 (to A.A.); and the Scientific Investigation Project PIC/IC/83037/2007. Further funding was obtained from the project “Microenvironment, Metabolism and Cancer,” partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the European Regional Development Fund. The work of J.M.C.-T. was supported by Grant PI12/00749-FEDER from the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness (Madrid, Spain). The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an associate laboratory of the Portuguese Ministry of Science, Technology, and Higher Education, which is partially supported by the Foundation for Science and Technology.por
dc.identifier.citationMelo, M., da Rocha, A. G., Vinagre, J., Batista, R., Peixoto, J., Tavares, C., Celestino, R., Almeida, A., Salgado, C., Eloy, C., Castro, P., Prazeres, H., Lima, J., Amaro, T., Lobo, C., Martins, M. J., Moura, M., Cavaco, B., Leite, V., … Soares, P. (2014). TERT Promoter Mutations Are a Major Indicator of Poor Outcome in Differentiated Thyroid Carcinomas. The Journal of Clinical Endocrinology & Metabolism, 99(5), E754–E765. https://doi.org/10.1210/jc.2013-3734
dc.identifier.doi10.1210/jc.2013-3734
dc.identifier.urihttp://hdl.handle.net/10400.22/5395
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherR. Paul Robertsonpor
dc.relation.publisherversionhttp://press.endocrine.org/doi/full/10.1210/jc.2013-3734por
dc.titleTERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomaspor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceUNITED STATESpor
oaire.citation.endPageE765por
oaire.citation.startPageE754por
oaire.citation.titleJournal of Clinical Endocrinology and Metabolismpor
oaire.citation.volume99por
person.familyNameCelestino
person.givenNameRicardo
person.identifier154697
person.identifier.ciencia-id301A-7536-FFE2
person.identifier.orcid0000-0002-9605-6433
person.identifier.ridJ-6048-2013
person.identifier.scopus-author-id57195924601
rcaap.rightsopenAccesspor
rcaap.typearticlepor
relation.isAuthorOfPublication46a9688a-c1bc-4e3d-a293-86f9b2c03058
relation.isAuthorOfPublication.latestForDiscovery46a9688a-c1bc-4e3d-a293-86f9b2c03058

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