TERT, BRAF and NRAS in primary thyroid cancer and metastatic disease

Authors and affiliations: 
Melo M^1,2,3,4, Gaspar da Rocha A^1,2,5, Batista R^1,2,6, Vinagre J^1,2,7, Martins MJ⁸, Costa G⁹, Ribeiro C³, Carrilho F³, Leite V^10,11,12, Lobo C¹³, Cameselle-Teijeiro JM¹⁴, Cavadas B^1,2, Pereira L^1,2,6, Sobrinho-Simões M^1,2,15,16, Soares P^1,2,15.

¹i3S - Instituto de Investigação e Inovação em Saúde.

²Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.

³Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

⁴Unit of Endocrinology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

⁵Public Health Unit, ACeS Baixo Mondego, Portugal.

⁶Medical Faculty, University of Porto, Porto, Portugal.

⁷Institute of Biomedical Sciences of Abel Salazar, University of Porto, Porto, Portugal.

⁸Department of Pathology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

⁹Department of Nuclear Medicine, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

¹⁰Unit for Investigation of Molecular Pathobiology, Portuguese Institute of Oncology - Lisbon Center, Lisbon, Portugal.

¹¹Faculty of Medical Sciences, University of Lisbon, Lisbon, Portugal.

¹²Department of Endocrinology, Portuguese Institute of Oncology - Lisbon Center, Lisbon, Portugal.

¹³Department of Pathology, Portuguese Institute of Oncology - Porto Center, Porto, Portugal.

¹⁴Department of Pathology, Clinical University Hospital, SERGAS, Medical Faculty, University of Santiago de Compostela, Santiago de Compostela, Spain.

¹⁵Department of Pathology and Oncology, Medical Faculty, University of Porto, Porto, Portugal.

¹⁶Department of Pathology, Hospital S. João, Porto, Portugal.

Abstract
CONTEXT: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype. OBJECTIVES: To evaluate the frequency of TERT promoter (TERTp), BRAF and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNM) and distant metastases.

DESIGN AND PATIENTS: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTC) (n=180), including 196 LNM and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue. RESULTS: We found the following mutation frequency in primary PTC, LNM and distant metastases, respectively: TERTp- 12.9%, 10.5%, and 52.4%; BRAF- 44.6%, 41.7%, and 23.8%; 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 PTC, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison to the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.

CONCLUSIONS: When the genotype of primary tumors is compared with the genotype of LNM, 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.

Journal: The Journal of Clinical Endocrinology & Metabolism

Link:: https://academic.oup.com/jcem/article-abstract/doi/10.1210/jc.2016-2785/3062306/TERT-BRAF-and-NRAS-in-primary-thyroid-cancer-and