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Ref Type Journal Article
PMID (35616103)
Authors Elisei R, Ciampi R, Matrone A, Prete A, Gambale C, Ramone T, Simeakis G, Materazzi G, Torregrossa L, Ugolini C, Romei C
Title Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib.
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Abstract Text 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.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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RET C634_A640dup duplication unknown RET C634_A640dup indicates the insertion of 7 duplicate amino acids, cysteine (C)-634 through alanine (A)-640, in the helical domain of the Ret protein (UniProt.org). C634_A640dup has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET D631_L633delinsS indel unknown RET D631_L633delinsS results in a deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 631 to 633, combined with the insertion of one serine (S) at the same site (UniProt.org). D631_L633delinsS has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET E632_A639delinsHR indel unknown RET E632_A639delinsHR results in a deletion of eight amino acids in the extracellular domain of the Ret protein from amino acids 632 to 639, combined with the insertion of a histidine (H) and an arginine (R) at the same site (UniProt.org). E632_A639delinsHR has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET E632_C634del deletion unknown RET E632_C634del results in the deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 632 to 634 (UniProt.org). E632_C634del has been identified in the scientific literature (PMID: 35616103, PMID: 31605946), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET G592_G607del deletion unknown RET G592_G607del results in the deletion of 16 amino acids in the extracellular domain of the Ret protein from amino acids 592 to 607 (UniProt.org). G592_G607del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET I590_G607del deletion unknown RET I590_G607del results in the deletion of 18 amino acids in the extracellular domain of the Ret protein from amino acids 590 to 607 (UniProt.org). I590_G607del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET L629_D631delinsH indel unknown RET L629_D631delinsH results in a deletion of three amino acids in the extracellular domain of the Ret protein from amino acids 629 to 631, combined with the insertion of one histidine (H) at the same site (UniProt.org). L629_D631delinsH has been identified in the scientific literature (PMID: 35616103, PMID: 31605946), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET S649_V650insLLLL insertion unknown RET S649_V650insLLLL results in the insertion of four amino acids in the helical domain of the Ret protein between amino acids 649 and 650 (UniProt.org).). S649_V650insLLLL has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
RET V899_E902del deletion unknown RET V899_E902del results in the deletion of four amino acids in the protein kinase domain of the Ret protein from amino acids 899 to 902 (UniProt.org). V899_E902del has been identified in the scientific literature (PMID: 35616103), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Apr 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET D631_L633delinsS thyroid gland medullary carcinoma predicted - sensitive Selpercatinib Case Reports/Case Series Actionable In a Phase I trial, Retevmo (selpercatinib) resulted in stable disease in the target lesions and a partial response in the non-target lesions in a patient with sporadic medullary thyroid cancer harboring RET D631_L633delinsS (PMID: 35616103; NCT03906331). 35616103
RET E632_L633del thyroid gland medullary carcinoma conflicting Selpercatinib Case Reports/Case Series Actionable In a Phase I trial, Retevmo (selpercatinib) resulted in a partial response in the target lesions and stable disease in the non-target lesions in a patient with sporadic medullary thyroid cancer harboring RET E632_L633del, and treatment continued for at least 17 months (PMID: 35616103; NCT03906331). 35616103