title: KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms arising in the gastrointestinal tract. GISTs express the KIT receptor tyrosine kinase, and many cases have activating mutations in the KIT juxtamembrane region. We now report an analysis of KIT cDNA and genomic sequences in eight GISTs that lack juxtamembrane region mutations. Six cases contained heterozygous exon 9 mutations in which six nucleotides, encoding Ala-Tyr, were duplicated. The other two cases contained homozygous exon 13 missense mutations, resulting in substitution of Glu for Lys(642), that were associated with constitutive KIT tyrosine phosphorylation. Sequence analysis of DNAs from nonneoplastic companion tissues revealed that both the exon 9 and exon 13 mutations were somatic. These are the first descriptions, in any tumor, of mutations in KIT exons encoding the C-terminal end of the extracellular domain and the first part of the split kinase domain. These findings indicate that KIT may be activated by mutations in at least three domains-extracellular, juxtamembrane, and kinase-in GISTs.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Lux
authors.forename: B P
authors.initials: BP
authors.lastname: Rubin
authors.forename: T L
authors.initials: TL
authors.lastname: Biase
authors.forename: C J
authors.initials: CJ
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Maclure
authors.forename: G
authors.initials: G
authors.lastname: Demetri
authors.forename: S
authors.initials: S
authors.lastname: Xiao
authors.forename: S
authors.initials: S
authors.lastname: Singer
authors.forename: C D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: J A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D005770:Gastrointestinal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016678:Genome; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010766:Phosphorylation; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit