title: Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors.
abstract: 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.
authors.affiliation: Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakai
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hashikura
authors.forename: Mizuka
authors.initials: M
authors.lastname: Ohkouchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Noriko
authors.initials: N
authors.lastname: Kajimoto
authors.forename: Yoshitane
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hao
authors.forename: Koji
authors.initials: K
authors.lastname: Isozaki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hirai
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D010375:Pedigree; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; C498826:nilotinib