TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas.
BACKGROUND
Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers.


OBJECTIVE
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).


METHODS
This was a retrospective observational study.


METHODS
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.


METHODS
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.
Institute of Molecular Pathology and Immunology of the University of Porto (M.Me., A.G.d.R., J.V., R.B., J.P., C.T., R.C., A.A., C.S., C.E., P.C., H.P., J.L., V.M., M.S.-S., P.S.), 4200-465 Porto, Portugal; Medical Faculty, University of Porto (A.G.d.R., C.T.), 4200-139 Porto, Portugal; Institute of Biomedical Sciences of Abel Salazar, University of Porto (J.V., A.A.), 4050-313 Porto, Portugal; Department of Pathology and Oncology, Medical Faculty, University of Porto (J.L., V.M., M.S.-S., P.S.), 4200-139 Porto, Portugal; Departments of Endocrinology, Diabetes, and Metabolism (M.Me., F.C., M.C.) and Pathology (M.J.M.), University and Hospital Center of Coimbra, 3000-075 Coimbra, Portugal; Unit of Endocrinology (M.Me., M.C.), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; School of Allied Health Sciences, ESTSP - Escola Superior de Tecnologia da Saúde do Porto (R.C.), Polytechnic of Porto, 4400-330 Vila Nova de Gaia, Portugal; Portuguese Institute of Oncology (H.P.), Coimbra Center, 3000-075 Coimbra, Portugal; Department of Pathology (T.A.), Hospital Pedro Hispano, 4464-513 Matosinhos, Portugal; Department of Pathology (C.L.), Portuguese Institute of Oncology, Porto Center, 4200-072 Porto, Portugal; Center for Investigation of Molecular Pathobiology (M.Mo., B.C., V.L.) and Department of Endocrinology (V.L.), Portuguese Institute of Oncology, Lisbon Center, 1099-023 Lisbon, Portugal; Center for the Study of Chronic Diseases (M.Mo., B.C., V.L.), Faculty of Medical Sciences, University of Lisbon, 1099-085 Lisbon, Portugal; Department of Pathology (J.M.C.-T.), Clinical University Hospital, Servicio Gallego de Salud - SERGAS, Medical Faculty, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain; and Department of Pathology (M.S.-S.), Hospital S. João, 4200-319 Porto, Portugal.
Miguel
M
Melo
Adriana Gaspar
AG
da Rocha
João
J
Vinagre
Rui
R
Batista
Joana
J
Peixoto
Catarina
C
Tavares
Ricardo
R
Celestino
Ana
A
Almeida
Catarina
C
Salgado
Catarina
C
Eloy
Patrícia
P
Castro
Hugo
H
Prazeres
Jorge
J
Lima
Teresina
T
Amaro
Cláudia
C
Lobo
Maria João
MJ
Martins
Margarida
M
Moura
Branca
B
Cavaco
Valeriano
V
Leite
José Manuel
JM
Cameselle-Teijeiro
Francisco
F
Carrilho
Manuela
M
Carvalheiro
Valdemar
V
Máximo
Manuel
M
Sobrinho-Simões
Paula
P
Soares
D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D019098:Telomerase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
C509186:TERT protein, human; D019098:Telomerase