title: KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs).
abstract: The tyrosine kinase receptor KIT plays a major role in gastrointestinal stromal tumors (GISTs) oncogenesis. Indeed, 95% of GISTs express KIT protein, and about 70% exhibit activating mutations of the KIT gene. However, little is known about KIT overexpression mechanisms in these tumors, and the correlation with KIT mutations. GISTs with mutations within exon 11 (n=12) or 9 (n=1) of KIT were compared with GISTs without KIT mutations in exons 9, 11, 13, and 17 (n=10), two of them had PDGFRA mutations. KIT amplification was studied by real-time PCR of KIT and beta-ACTIN genes, and by fluorescence in situ hybridization (FISH) using KIT and chromosome 4 centromere specific probes. KIT transcripts and protein expression were quantified by reverse transcription real-time PCR and Western blot respectively. Genomic analysis revealed a single mutated GIST with KIT amplification. KIT protein and RNA levels were highly variable in GISTs but closely correlated (r=0.82, P<1.10(-5)), and were higher in GISTs with KIT mutations (P=0.07 and P=0.03 respectively). In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription.
authors.affiliation: Biochemistry and Molecular Biology Department, Paul Brousse Hospital, AP-HP, INSERM U602, Paris Sud University, Villejuif 94804, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Tabone
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théou
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Raphael
authors.initials: R
authors.lastname: Saffroy
authors.forename: Laure
authors.initials: L
authors.lastname: Deville
authors.forename: Catherine
authors.initials: C
authors.lastname: Julié
authors.forename: Patrice
authors.initials: P
authors.lastname: Callard
authors.forename: Anne
authors.initials: A
authors.lastname: Lavergne-Slove
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Antoinette
authors.initials: A
authors.lastname: Lemoine
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
mesh_terms: D000328:Adult; D000368:Aged; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha