Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas

send to a friend share this

Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas

Monday, 17.07.2017

Familial nonmedullary thyroid carcinoma (FNMTC) accounts for nearly 5% of all thyroid carcinomas of follicular cell origin. The genes causing FNMTC identified to date are only involved in a small fraction of the families and, thus, the molecular basis of this disease remains mainly unknown.

The aim of this study was to investigate the role of TERT promoter and EIF1AX germline and somatic mutations in families with FNMTC.

The results of this study suggest that germline TERT promoter and EIF1AX mutations are not frequently involved in FNMTC aetiology. Additionally, no somatic EIF1AX mutations were identified in the familial thyroid tumours. However, we detected for the first time in familial thyroid cancer somatic TERT promoter alterations, in concomitance with BRAF mutations, which appear to be associated with progression and more advanced stages of the disease.

 

This project was funded by Televisão Independente (TVI), Núcleo Regional Sul da Liga Portuguesa Contra o Cancro (NRS-LPCC) and Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG).

 

Authors and Affiliations:

Inês J. Marques1,4,5, Margarida M. Moura1, Rafael Cabrera3, António E. Pinto3, Joana Simões-Pereira1,2,5, Catarina Santos6, Francisco D. Menezes7, Diana Montezuma7, Rui Henrique7,8, Manuel R. Teixeira6,8, Valeriano Leite1,2,5, Branca M. Cavaco1

 

1Unidade de Investigação em Patobiologia Molecular (UIPM),

2Serviço de Endocrinologia e

3Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; 4Chronic Diseases Research Centre (CEDOC) e

5Nova Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal;

6Serviço de Genética e 

7Serviço de Anatomia Patológica, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal; 

8Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.

 

Abstract:

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 -positive samples were also positive for BRAF p.Val600Glu, and this co-occurrence was found to be statistically significant (=.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.

 

Journal: Clinical Endocrinology

 

Link: http://onlinelibrary.wiley.com/doi/10.1111/cen.13375/abstract