Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib

J Clin Endocrinol Metab. 2022 Jul 14;107(8):2195-2202. doi: 10.1210/clinem/dgac325.


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.

Keywords: RET indels; NGS; medullary thyroid carcinoma; next-generation sequencing; selpercatinib; tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Neuroendocrine* / genetics
  • Humans
  • Mutation
  • Prevalence
  • Proto-Oncogene Proteins c-ret / genetics
  • Pyrazoles
  • Pyridines
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / epidemiology
  • Thyroid Neoplasms* / genetics


  • Pyrazoles
  • Pyridines
  • selpercatinib
  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Thyroid cancer, medullary