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TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease
Miguel Melo1,2,3,4, Adriana Gaspar da Rocha1,2,5, Rui Batista1,2,6
1i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.
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 (LNMs), and distant metastases.
Design And Patients:
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.
Results:
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.
Conclusions:
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.
Insights
Key mutations in thyroid cancer differ between primary tumors and distant metastases. TERT promoter mutations increase in distant metastases, while BRAF mutations decrease, suggesting a role in metastatic progression.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Thyroid cancer metastasis genotype is poorly understood.
- Key mutations like TERT promoter, BRAF, and NRAS are crucial in thyroid cancer development.
- Understanding mutation patterns in metastases is vital for targeted therapies.
Purpose of the Study:
- To determine the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas.
- To compare mutation profiles between primary tumors, lymph node metastases (LNMs), and distant metastases.
- To investigate the relationship between primary tumor genotype and metastatic lesions.
Main Methods:
- Mutation analysis of TERTp, BRAF, and NRAS in 437 tissue samples from 204 thyroid cancer patients.
- Analysis included primary tumors, LNMs, and distant metastases (radioiodine-refractory).
- Genomic DNA was extracted and sequenced for mutation detection.
Main Results:
- TERTp mutations were found in 12.9% of primary tumors, 10.5% of LNMs, and 52.4% of distant metastases.
- BRAF mutations decreased from 44.6% in primary tumors to 23.8% in distant metastases.
- NRAS mutations increased from 1.2% in primary tumors to 14.3% in distant metastases.
- High concordance between primary tumors and LNMs, but low concordance with distant metastases.
- Distant metastases showed enrichment of TERTp mutations and a decrease in BRAF mutations compared to primary tumors.
Conclusions:
- Thyroid cancer metastasis genotype differs significantly from primary tumors, especially in distant sites.
- TERTp mutations are enriched in distant metastases and may contribute to metastatic spread.
- BRAF mutations are less frequent in distant metastases, suggesting a potential shift in driving mutations during progression.
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