TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.
Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype.



To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases.



Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue.



We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.



When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Department of Endocrinology, Diabetes, and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.|Unit of Endocrinology, Faculty of Medicine, University of Coimbra, Coimbra 3000-075, Portugal.
Miguel
M
Melo
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Public Health Unit, ACeS Baixo Mondego, Coimbra 3040-006, Portugal.
Adriana
A
Gaspar da Rocha
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Medical Faculty, University of Porto, Porto 4200-319, Portugal.
Rui
R
Batista
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Institute of Biomedical Sciences of Abel Salazar, University of Porto, Porto 4050-313, Portugal.
João
J
Vinagre
Department of Pathology, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.
Maria João
MJ
Martins
Department of Nuclear Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.
Gracinda
G
Costa
Department of Endocrinology, Diabetes, and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.
Cristina
C
Ribeiro
Department of Endocrinology, Diabetes, and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-075, Portugal.
Francisco
F
Carrilho
Unit for Investigation of Molecular Pathobiology, Portuguese Institute of Oncology-Lisbon Center, Lisbon 1099-023, Portugal.|Faculty of Medical Sciences, University of Lisbon, Lisbon 1169-056, Portugal.|Department of Endocrinology, Portuguese Institute of Oncology-Lisbon Center, Lisbon 1099-023, Portugal.
Valeriano
V
Leite
Department of Pathology, Portuguese Institute of Oncology-Porto Center, Porto 4200-072, Portugal.
Cláudia
C
Lobo
Department of Pathology, Clinical University Hospital, Servizo Galego de Saúde (SERGAS), Medical Faculty, University of Santiago de Compostela, Santiago de Compostela 15706, Spain.
José Manuel
JM
Cameselle-Teijeiro
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.
Bruno
B
Cavadas
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Medical Faculty, University of Porto, Porto 4200-319, Portugal.
Luísa
L
Pereira
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto 4200-319, Portugal.|Department of Pathology, Hospital São João, Porto 4200-319, Portugal.
Manuel
M
Sobrinho-Simões
i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.|Institute of Molecular Pathology and Immunology, University of Porto, Porto 4200-135, Portugal.|Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto 4200-319, Portugal.
Paula
P
Soares
D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary; D002291:Carcinoma, Papillary; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary
D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human