Reference Detail

Ref Type

Journal Article

PMID

(35689816)

Authors

Ma X, Ma X, Chin L, Zhu Z, Han H

Title

A Novel Germline Deletion of p.C630 in RET Causes MTC and Promotes Cell Proliferation and Sensitivity to Pralsetinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical endocrinology and metabolism	107	9	2022 Aug 18	2636-2643	J Clin Endocrinol Metab

URL

Abstract Text

Medullary thyroid cancer (MTC) is usually caused by gain-of-function mutations in the proto-oncogene RET.This study aimed to determine the underlying mechanism in a male patient diagnosed with MTC at age 51 years.Genomic DNA extracted from leukocytes or tumor tissues of patients was used for next-generation sequencing (NGS)-panel sequencing and Sanger sequencing. Wild-type (WT) and p.C630 deletion RET were expressed in HEK 293T cells. Activation of phosphorylation of the crucial tyrosine-905 of RET and MAPK/ERK was analyzed by Western blotting. The effect of RET mutants on cell viability and colony formation ability was determined by CCK8 assay and a colony forming assay.NGS-Panel sequencing revealed a 3-nucleotide/1-amino acid C630 in-frame deletion in exon 11 of RET (c.1887_1889delGTG p.C630del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.C630del RET mutant than in WT RET, indicating ligand-independent activation of the Ret protein tyrosine kinase. Furthermore, p.C630del RET mutant induced strong activation of the MAPK/ERK pathway. In addition, p.C630del RET mutant cells exhibited increased HEK 293T cell viability and colony formation compared with WT RET cells. Pralsetinib (BLU-667), a highly selective RET inhibitor, inhibited the viability of WT RET and p.C630del RET mutant-transfected HEK 293T cells (IC50s: 18.54 and 16.49 µM after treatment for 24 hours), followed by inhibition of the RET-induced MAPK/ERK pathway.The finding in our patient with MTC was a 3-base-pair deletion in exon 11 of RET, a p.C630 deletion not previously reported. The p.C630del RET stimulates cell proliferation by increasing ligand-independent phosphorylation and activation of MAPK/ERK pathway, demonstrating the pathogenic nature of the mutation. We therefore recommend screening panel sequence of RET in MTC patients with indications of a genetic cause.

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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	C630del	deletion	gain of function	RET C630del results in the deletion of an amino acid in the cysteine-rich region of the Ret protein at amino acid 630 (UniProt.org). C630del results in increased Ret phosphorylation, downstream signaling, viability, and colony formation in cultured cells (PMID: 35689816).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C630del	Advanced Solid Tumor	sensitive	Pralsetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Gavreto (pralsetinib) treatment inhibited Ret phosphorylation and downstream signaling and resulted in decreased cell viability and colony formation in cells expressing RET C630del in culture (PMID: 35689816).	35689816