KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neo plasms arising in the gastrointestinal tract. GISTs express the KIT recepto r tyrosine kinase, and many cases have activating mutations in the KIT juxt amembrane region. We now report an analysis of KIT cDNA and genomic sequenc es in eight GISTs that lack juxtamembrane region mutations. Six cases conta ined heterozygous exon 9 mutations in which six nucleotides, encoding Ala-T yr, were duplicated. The other two cases contained homozygous exon 13 misse nse mutations, resulting in substitution of Glu for Lys(642), that were ass ociated with constitutive KIT tyrosine phosphorylation. Sequence analysis o f DNAs from nonneoplastic companion tissues revealed that both the exon 9 a nd 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 extrac ellular domain and the first part of the split kinase domain. These finding s indicate that KIT may be activated by mutations in at least three domains -extracellular, juxtamembrane, and kinase-in GISTs.