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Ref Type Journal Article
PMID (16143141)
Authors Hartmann K, Wardelmann E, Ma Y, Merkelbach-Bruse S, Preussner LM, Woolery C, Baldus SE, Heinicke T, Thiele J, Buettner R, Longley BJ
Title Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis.
Journal Gastroenterology
Vol 129
Issue 3
Date 2005 Sep
URL
Abstract Text Gastrointestinal stromal tumors (GISTs) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTs respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTs and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors.

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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
KIT D419del deletion unknown KIT D419del results in the deletion of an amino acid in Ig-like C2-type domain 5 of the Kit protein at amino acid 419 (UniProt.org). The functional effect of D419del is conflicting, as D419del has been reported to result in ligand-independent phosphorylation of Kit (PMID: 16143141, PMID: 15618474), and to result in lack of Kit phosphorylation and lack of cytokine-independent growth in cell culture (PMID: 31182436), and leads to Kit inactivation in response to Ptpre similar to wild-type Kit in cultured cells (PMID: 33732906).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT D419del Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Biochemical Actionable In a preclinical study, Gleevec (imatinib) treatment inhibited Kit autophosphorylation in transformed cells expressing KIT D419del in culture (PMID: 16143141). 16143141