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Effect of BRAFV600E and TERT Promoter Mutations on Thyroglobulin Response in Patients With Distant-Metastatic
Zhuan-Zhuan Mu1, Ying-Qiang Zhang1, Di Sun1
1Department of Nuclear Medicine, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences and PUMC, Beijing, China; Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Beijing, China.
Objective:
To assess the impact of serine/threonine-protein kinase B-Raf (BRAF) V600E and telomerase reverse transcriptase (TERT) promoter mutations in patients with distant-metastatic differentiated thyroid cancer (DM-DTC) based on thyroglobulin (Tg) response to radioactive iodine (RAI) therapy.
Methods:
The BRAFV600E and TERT mutations in primary tumors or metastatic lymph nodes of 114 patients with DM-DTC were retrospectively examined. RAI avidity was evaluated using a posttreatment iodine-131 whole-body scan. The Tg response was dynamically assessed at a median follow-up period of 56.50 months (interquartile range, 28.43-97.98 months).
Results:
BRAFV600E was detected in 38.6% of cases, the TERT mutation in 21.1% of cases, and both the BRAFV600E and TERT mutations in 14.9% of cases. Patients with both the mutations tended to be older at diagnosis (P < .001) and less multifocal (P = .011) and have more aggressive histologic subtypes (P = .011) and a higher Ki-67 index (P = .003). Patients with neither mutation tended to be have more RAI avidity than those with either the BRAFV600E mutation alone or both the mutations (P = .001 and .001, respectively). Patients with both the mutations exhibited a more unfavorable Tg response than those without both the mutations and those with the BRAFV600E mutation alone (P = .001 and .013, respectively). The Tg progression-free survival was shorter in patients with the TERT mutation alone than in those with neither mutation (P = .021), and it tended to be shorter when it coexisted with the BRAFV600E mutation (P < .001); however, no significant difference was observed between those with the BRAFV600E mutation alone and those with neither mutation (P = .890).
Conclusion:
The coexistence of the BRAFV600E and TERT promoter mutations synergistically induce the loss of RAI avidity and leads to an undesirable Tg response in patients with DM-DTC. The TERT promoter mutation appears to affect Tg response more than the BRAFV600E mutation.
Insights
The BRAF V600E and TERT promoter mutations in distant-metastatic differentiated thyroid cancer (DM-DTC) reduce radioactive iodine (RAI) avidity. Co-occurring mutations worsen thyroglobulin (Tg) response, indicating poorer outcomes.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Distant-metastatic differentiated thyroid cancer (DM-DTC) presents therapeutic challenges.
- Genetic mutations, including BRAF V600E and TERT promoter mutations, are implicated in DTC progression.
- The impact of these mutations on response to radioactive iodine (RAI) therapy requires further elucidation.
Purpose of the Study:
- To investigate the combined and individual effects of BRAF V600E and TERT promoter mutations on RAI avidity and thyroglobulin (Tg) response in DM-DTC patients.
- To assess the prognostic significance of these mutations in the context of RAI therapy outcomes.
Main Methods:
- Retrospective analysis of 114 DM-DTC patients.
- BRAF V600E and TERT promoter mutations were identified in primary tumors or metastatic lymph nodes.
- Radioactive iodine (RAI) avidity was assessed via iodine-131 whole-body scans post-treatment.
- Thyroglobulin (Tg) response and progression-free survival were evaluated over a median follow-up of 56.50 months.
Main Results:
- BRAF V600E mutations were found in 38.6%, TERT mutations in 21.1%, and both in 14.9% of patients.
- Co-occurrence of BRAF V600E and TERT mutations was associated with older age at diagnosis, less multifocality, aggressive histology, and higher Ki-67 index.
- Patients with neither mutation showed higher RAI avidity compared to those with BRAF V600E alone or both mutations (P=.001).
- The presence of both mutations led to a significantly poorer Tg response compared to those with neither or BRAF V600E alone (P=.001 and P=.013, respectively).
- TERT mutation alone was associated with shorter Tg progression-free survival (P=.021), and this effect was more pronounced when coexisting with BRAF V600E (P<.001).
Conclusions:
- The coexistence of BRAF V600E and TERT promoter mutations synergistically reduces RAI avidity and leads to an unfavorable Tg response in DM-DTC.
- The TERT promoter mutation appears to exert a more significant negative impact on Tg response than the BRAF V600E mutation alone.
- These genetic alterations are critical factors influencing treatment outcomes in DM-DTC patients undergoing RAI therapy.
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