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Ref Type Journal Article
PMID (32284345)
Authors Zhao Z, Fu T, Gao J, Xu Y, Wu X, Chen W, Li X, Yu R, Shao YW, Li M, Yao Y
Title Identifying novel oncogenic RET mutations and characterising their sensitivity to RET-specific inhibitors.
Journal Journal of medical genetics
Vol
Issue
Date 2020 Apr 13
URL
Abstract Text Rearranged during transfection (RET) is a well-known proto-oncogene. Multiple RET oncogenic alterations have been identified, including fusions and mutations. Although RET fusions have been reported in multiple cancers, RET mutations were mainly found in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. RET mutations in other cancers were underinvestigated and their functional annotation was less well studied.We retrospectively reviewed next-generation sequencing data from 37 056 patients with cancer to search for RET mutations. We excluded patients with other co-occurring known driver mutations to enrich potential activating RET mutations for further analysis. Moreover, we performed in vitro functional validation of the oncogenic property of several high frequent and novel RET mutants and their sensitivity to RET-specific inhibitors LOXO-292 and BLU-667.Within 560 (1.5%) patients with cancer who harbour RET mutations, we identified 380 distinct RET mutation sites, including 252 sites without co-occurring driver mutations. RET mutations were more frequently found in thyroid cancer, mediastinal tumour and several other cancers. The mutation sites spread out through the whole protein with a few hotspots within the kinase domain. In addition, we functionally validated that 898-901del, T930P and T930K were novel RET-activating mutations and they were all sensitive to RET inhibitors.Our results demonstrated the frequency of RET mutations across different cancers. We reported and/or validated several previously uncharacterised RET oncogenic mutations and demonstrated their sensitivity to RET-specific inhibitors. Our results help to stratify patients with cancer based on their RET mutation status and potentially provide more targeted treatment options.

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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 D898_E901del deletion gain of function RET D898_E901del results in the deletion of four amino acids in the protein kinase domain of the Ret protein from amino acids 898 to 901 (UniProt.org). D898_E901del confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and cytokine-independent growth in culture (PMID: 32284345).
RET E136K missense unknown RET E136K lies within the extracellular domain of the Ret protein (UniProt.org). E136K has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized, and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2022).
RET K662M missense unknown RET K662M lies within the cytoplasmic domain of the Ret protein (UniProt.org). K662M has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2022).
RET R133C missense unknown RET R133C lies within the extracellular domain of the Ret protein (UniProt.org). R133C has been identified in sequencing studies (PMID: 32284345, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2022).
RET R177W missense unknown RET R177W lies within the cadherin domain of the Ret protein (UniProt.org). R177W has been identified in sequencing studies (PMID: 34741450, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2022).
RET R721W missense unknown RET R721W lies within the cytoplasmic domain of the Ret protein (UniProt.org). R721W has been identified in sequencing studies (PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2022).
RET T742M missense unknown RET T742M lies within the protein kinase domain of the Ret protein (UniProt.org). T742M has been identified in the scientific literature (PMID: 31712133, PMID: 32284345), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2022).
RET T930K missense gain of function - predicted RET T930K lies within the protein kinase domain of the Ret protein (UniProt.org). T930K results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to lead to a gain of Ret protein function.
RET T930M missense no effect - predicted RET T930M lies within the protein kinase domain of the Ret protein (UniProt.org). T930M results in Erk phosphorylation similar to wild-type Ret and does not result in cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to have no effect on Ret protein function.
RET T930P missense gain of function - predicted RET T930P lies within the protein kinase domain of the Ret protein (UniProt.org). T930P results in Erk phosphorylation similar to wild-type Ret but cytokine-independent growth in culture (PMID: 32284345), and therefore, is predicted to lead to a gain of Ret protein function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET D898_E901del Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET D898_E901del in culture (PMID: 32284345). 32284345
RET T930P Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited growth of transformed cells expressing RET T930P in culture (PMID: 32284345). 32284345
RET D898_E901del Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET D898_E901del in culture (PMID: 32284345). 32284345
RET M918T Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET M918T in culture (PMID: 32284345). 32284345
RET T930P Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited growth of transformed cells expressing RET T930P in culture (PMID: 32284345). 32284345
RET M918T Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Erk phosphorylation and growth of transformed cells expressing RET M918T in culture (PMID: 32284345). 32284345
RET T930K Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited growth of transformed cells expressing RET T930K in culture (PMID: 32284345). 32284345
RET T930K Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited growth of transformed cells expressing RET T930K in culture (PMID: 32284345). 32284345