KIT Extracellular and Kinase Domain Mutations in Gastrointestinal Stromal Tumors

• Published in: The American journal of pathology Vol. 156; no. 3; pp. 791 - 795
• Main Authors: Lux, Marcia L., Rubin, Brian P., Biase, Tara L., Chen, Chang-Jie, Maclure, Timothy, Demetri, George, Xiao, Sheng, Singer, Samuel, Fletcher, Christopher D.M., Fletcher, Jonathan A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2000; ASIP; American Society for Investigative Pathology
• Subjects: Amino Acid Sequence; Base Sequence; Biological and medical sciences; DNA Primers - chemistry; DNA, Complementary - metabolism; DNA, Neoplasm - analysis; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Neoplasms - chemistry; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Genome; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Medical sciences; Molecular Sequence Data; Mutation, Missense; Phosphorylation; Point Mutation; Proto-Oncogene Proteins c-kit - analysis; Proto-Oncogene Proteins c-kit - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm - analysis; Short Communications; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Stromal Cells - chemistry; Stromal Cells - metabolism; Stromal Cells - pathology; Tumors; Tyrosine - metabolism; Human; Enzyme; Transferases; Stroma; Reverse transcription; Gastrointestinal; Carcinogenesis; Polymerase chain reaction; Pathology; Fluorescence in situ hybridization; Digestive diseases; Intestinal disease; Tumor; Mutation; Molecular biology; Protein-tyrosine kinase; Sequencing; Stromal tumor; Gastric disease; Biological receptor
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64946-2

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.