KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs)

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.