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Ref Type Journal Article
PMID (22083669)
Authors Nakai M, Hashikura Y, Ohkouchi M, Yamamura M, Akiyama T, Shiba K, Kajimoto N, Tsukamoto Y, Hao H, Isozaki K, Hirai T, Hirota S
Title Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors.
Journal Vol Issue Date Pages Journal Short Title
Laboratory investigation; a journal of technical methods and pathology 92 3 2012 Mar 451-7 Lab Invest
URL
Abstract Text We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.

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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 Y553C missense gain of function - predicted KIT Y553C lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). Y553C is predicted to lead to a gain of Kit protein function as a corresponding mouse variant (Y552C) results in IL3-independent growth in cultured cells (PMID: 22083669).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT Y553C Advanced Solid Tumor predicted - sensitive Nilotinib Preclinical - Cell culture Actionable In a preclinical study, Tasigna (nilotinib) treatment inhibited Kit autophosphorylation and viability of cells expressing KIT Y552C (corresponding to Y553C in human) in culture (PMID: 22083669). 22083669
KIT Y553C Advanced Solid Tumor predicted - sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) treatment inhibited Kit autophosphorylation and viability of cells expressing KIT Y552C (corresponding to Y553C in human) in culture (PMID: 22083669). 22083669