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Updated: May 4, 2026
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic
Zhuanzhuan Mu1,2, Xin Zhang1,2, Dongquan Liang3
1Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College (PUMC) Hospital, Chinese Academy of Medical Sciences & PUMC, Beijing 100730, China.
Objective:
Patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.
Methods:
Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel (ThyroLead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification (MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.
Results:
A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIR-DTC. Genetic alterations were identified in 90% of all the patients, with BRAF (59.7% vs. 17.3%), TERT promoter (43.9% vs. 7.4%), and TP53 mutations (11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions (15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness (P<0.001), with an odds ratio (OR) of high to low MRS of 7.52 [95% confidence interval (95% CI), 3.96-14.28; P<0.001] and an OR of intermediate to low MRS of 3.20 (95% CI, 1.01-10.14; P=0.041).
Conclusions:
Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.
Insights
Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) is linked to specific genetic mutations, including BRAF and TERT promoter. Molecular risk stratification (MRS) can predict outcomes and guide treatment for RAIR-DTC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) presents limited therapeutic options.
- The genetic underpinnings of RAI refractoriness in DTC are not fully understood.
- Early identification and targeted therapies are crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the correlation between genetic alterations and RAI refractoriness in metastatic DTC.
- To develop and validate a molecular risk stratification (MRS) model for RAIR-DTC.
Main Methods:
- Next-generation sequencing of a 26-gene panel (ThyroLead) was performed on 220 adult patients with metastatic DTC.
- Patients were categorized into RAIR-DTC and non-RAIR groups.
- Molecular risk stratification (MRS) was developed based on identified genetic alterations and RAI refractoriness.
Main Results:
- Genetic alterations were found in 90% of patients, with BRAF, TERT promoter, and TP53 mutations significantly more prevalent in the RAIR-DTC group.
- RET fusions were more common in the non-RAIR group.
- BRAF and TERT promoter mutations independently predicted RAIR-DTC, accounting for 67.6% of cases. MRS showed a strong association with RAI refractoriness (P<0.001).
Conclusions:
- Specific molecular alterations, particularly BRAF and TERT promoter mutations, are strongly associated with RAI refractoriness in DTC.
- The developed MRS model is a valuable tool for prognosticating clinical outcomes.
- MRS can aid in directing precision-based therapeutic interventions for RAIR-DTC.
