Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas

• Published in: Clinical endocrinology (Oxford) Vol. 87; no. 4; pp. 394 - 399
• Main Authors: Marques, Inês J., Moura, Margarida M., Cabrera, Rafael, Pinto, António E., Simões‐Pereira, Joana, Santos, Catarina, Menezes, Francisco D., Montezuma, Diana, Henrique, Rui, Rodrigues Teixeira, Manuel, Leite, Valeriano, Cavaco, Branca M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2017
• Subjects: Adult; BRAF; Carcinoma, Papillary - genetics; Deoxyribonucleic acid; DNA; EIF1AX; Eukaryotic Initiation Factor-1 - genetics; Familial nonmedullary thyroid carcinoma; Female; Genetic Predisposition to Disease - genetics; Humans; Male; Middle Aged; Mutation; Mutation hot spots; Nucleotide sequence; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins B-raf - genetics; RAS; Statistical analysis; Telomerase - genetics; TERT promoter mutations; Thyroid cancer; Thyroid Cancer, Papillary; Thyroid carcinoma; Thyroid gland; Thyroid Neoplasms - genetics; Thyroxine; Tumors; TERT promoter mutations; Familial nonmedullary thyroid carcinoma; BRAF; RAS; EIF1AX
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/cen.13375

Summary Objective The genes causing familial nonmedullary thyroid carcinoma (FNMTC) identified to date are only involved in a small fraction of the families. Recently, somatic mutations in TERT promoter region and in EIF1AX gene were reported in thyroid tumours of undefined familial status. The aim of this study was to investigate the role of TERT and EIF1AX mutations in familial thyroid tumours. Design The promoter region of TERT was sequenced in leucocyte DNA of the probands from 75 FNMTC families. In thyroid tumours from 54 familial cases, we assessed somatic TERT promoter, RAS and BRAF hotspot mutations, and the whole EIF1AX gene. Results No potentially pathogenic germline variants were identified in TERT in the 75 FNMTC families’ probands. In the 54 carcinomas, we identified five cases (9%) with hotspot somatic TERT promoter mutations. BRAF mutations were found in 41% of the tumours. All TERT‐positive samples were also positive for BRAF p.Val600Glu, and this co‐occurrence was found to be statistically significant (P=.008). RAS mutations were detected in four tumours wild‐type for TERT (7%). Evaluation of tumour mutation data together with the patients’ clinicopathological features revealed a significant correlation between TERT plus BRAF mutations and advanced tumour stage (T4) (P=.020). No mutations were identified in EIF1AX. Conclusions The results of this study suggest that TERT promoter and EIF1AX mutations are not frequently involved in FNMTC aetiology. However, we show for the first time that TERT alterations are associated with familial thyroid tumour progression. Our data also suggest that TERT mutations are more often found in concomitance with BRAF mutations in advanced stages of FNMTC.