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Identification of somatic TERT promoter mutations in familial nonmedullary thyroid carcinomas
Inês J Marques1,2,3, Margarida M Moura1, Rafael Cabrera4
1Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal.
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.
Insights
TERT promoter mutations are not common in familial nonmedullary thyroid carcinoma (FNMTC). However, TERT alterations correlate with advanced tumor stage and often co-occur with BRAF mutations in FNMTC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Familial nonmedullary thyroid carcinoma (FNMTC) genetic basis remains largely unknown, with identified genes explaining only a small fraction of cases.
- Recent studies identified TERT promoter and EIF1AX mutations in sporadic thyroid tumors, prompting investigation into their role in familial forms.
Purpose of the Study:
- To investigate the involvement of TERT promoter and EIF1AX gene mutations in the etiology of familial thyroid tumors.
- To determine the association of these mutations with tumor progression and clinicopathological features in FNMTC.
Main Methods:
- Sequencing of the TERT promoter region in germline DNA from 75 FNMTC probands.
- Analysis of somatic mutations in TERT promoter, RAS, BRAF, and the EIF1AX gene in tumor DNA from 54 familial thyroid cancer cases.
Main Results:
- No pathogenic germline TERT variants were found in FNMTC families.
- Somatic TERT promoter mutations were identified in 9% of familial thyroid tumors, significantly associated with BRAF V600E mutations (P=.008).
- TERT and BRAF co-mutations correlated with advanced tumor stage (T4) (P=.020); no EIF1AX mutations were detected.
Conclusions:
- TERT promoter and EIF1AX mutations are not frequent drivers of FNMTC.
- TERT alterations are linked to familial thyroid tumor progression and are often found with BRAF mutations in advanced disease stages.
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