title: KIT activation is a ubiquitous feature of gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. Most GISTs express the KIT receptor tyrosine kinase protein, and a subset of GISTs contain activating mutations within the KIT juxtamembrane region. We evaluated 48 GISTs, including 10 benign, 10 borderline, and 28 malignant cases, to determine whether KIT expression and activation are general properties of these tumors. Immunohistochemical KIT expression was demonstrated in each case. Somatic KIT mutations were found in 44 tumors (92%), of which 34 (71%) had juxtamembrane region mutations. Other GISTs had KIT mutations in the extracellular region (n = 6) and in two different regions in the tyrosine kinase domain (n = 4). Contrary to previous reports, KIT mutations were not identified preferentially in higher-grade tumors: indeed, they were found in each of 10 histologically benign GISTs. Notably, mutations in all KIT domains were associated with high-level KIT activation/phosphorylation, and KIT activation was also demonstrated in the four GISTs that lacked detectable KIT genomic and cDNA mutations. These studies underscore the role of KIT activation in GIST pathogenesis, and they suggest that activated KIT might represent a universal therapeutic target in GISTs.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Rubin
authors.forename: S
authors.initials: S
authors.lastname: Singer
authors.forename: C
authors.initials: C
authors.lastname: Tsao
authors.forename: A
authors.initials: A
authors.lastname: Duensing
authors.forename: M L
authors.initials: ML
authors.lastname: Lux
authors.forename: R
authors.initials: R
authors.lastname: Ruiz
authors.forename: M K
authors.initials: MK
authors.lastname: Hibbard
authors.forename: C J
authors.initials: CJ
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Xiao
authors.forename: D A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: G D
authors.initials: GD
authors.lastname: Demetri
authors.forename: C D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: J A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit