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Updated: Aug 10, 2025
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive
Laura Boucai1, Mahesh Saqcena2, Fengshen Kuo3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness.
Experimental Design:
Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio.
Results:
ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity.
Conclusions:
ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.
Insights
Genomic and transcriptomic factors influence response to radioiodine (RAI) therapy in metastatic thyroid cancer. Lower MAPK pathway activity and higher thyroid differentiation predict exceptional RAI response, while BRAFV600E and 1q-gain indicate resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Radioiodine (RAI) therapy is a standard treatment for metastatic thyroid cancer.
- Predicting response to RAI remains a significant clinical challenge.
- Understanding the molecular underpinnings of RAI resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To identify genomic and transcriptomic factors associated with response to RAI treatment in metastatic thyroid cancer.
- To investigate whether high MAPK pathway output correlates with RAI refractoriness.
- To compare molecular profiles of exceptional responders versus nonresponders.
Main Methods:
- Retrospective case-control study design.
- Analysis of genomic and transcriptomic characteristics.
- Matching exceptional responders (ER) and nonresponders (NR) by histology and stage.
- Definition of exceptional response based on RECIST v1.1 tumor volume reduction.
Main Results:
- Exceptional responders (ER) showed enrichment for MAPK-activating mutations (RAS, class 2 BRAF, RTK fusions).
- Nonresponders (NR) were associated with BRAFV600E, 1q-gain, and mutations in splicing/PI3K pathways.
- ER tumors exhibited lower MAPK transcriptional output and higher thyroid differentiation scores (TDS) compared to NR.
- BRAFV600E tumors with 1q-gain displayed lower TDS and transcriptomic signatures linked to metastasis.
Conclusions:
- Distinct molecular profiles differentiate RAI responders from nonresponders.
- Lower MAPK pathway activity and higher TDS are associated with exceptional RAI response.
- BRAFV600E combined with 1q-gain may predict RAI refractoriness and increased metastatic potential.
- Molecular profiling can aid in predicting RAI therapy response in thyroid cancer.
