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Updated: Sep 22, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib
Rossella Elisei1, Raffaele Ciampi1, Antonio Matrone1
1Unit of Endocrinology, Department of Clinical and Experimental Medicine, University-Hospital of Pisa, 56124 Pisa, Italy.
Context:
Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET-specific inhibitors in patients harboring RET indels has been provided.
Objective:
We present an update on the prevalence of RET indels in medullary thyroid cancer (MTC) and describe the efficacy of selpercatinib in patients with advanced MTC with RET indels.
Methods:
The MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by MutationTaster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel were treated with selpercatinib.
Results:
Among 178 RET-positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by MutationTaster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment.
Conclusion:
These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indel-positive patients showed a partial response to the treatment with a highly selective RET inhibitor; thus, these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended.
Insights
RET indels are not infrequent in medullary thyroid cancer and indicate aggressive disease. Two patients with RET indels responded well to selpercatinib, suggesting these are actionable mutations.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- RET alterations, primarily single nucleotide variants (SNVs), are common in medullary thyroid cancer (MTC).
- The prevalence and clinical significance of RET insertions/deletions (indels) remain less understood.
- Efficacy data for RET-specific inhibitors in patients with RET indels are lacking.
Purpose of the Study:
- To determine the prevalence of RET indels in MTC.
- To evaluate the efficacy of selpercatinib in advanced MTC patients with RET indels.
- To assess if RET indels represent actionable mutations.
Main Methods:
- Targeted sequencing of MTC tissues from 287 patients using Ion S5.
- Functional evaluation of indels using MutationTaster.
- Clinical and pathological data collection for MTC patients with RET indels.
- Treatment analysis of two patients with RET indels receiving selpercatinib.
Main Results:
- RET indels were identified in 31 out of 178 (17.4%) RET-positive MTC cases.
- Nine novel, disease-causing indels were discovered.
- Patients with RET indels presented with more aggressive disease.
- Two patients with RET indels showed a partial response to selpercatinib.
Conclusions:
- RET indels are relatively frequent in MTC and associated with aggressive disease.
- Selpercatinib demonstrated efficacy in patients with RET indels, classifying them as actionable mutations.
- Comprehensive analysis of the entire RET gene is recommended to identify all relevant alterations.
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