title: KIT gene in pediatric osteosarcomas: could it be a new therapeutic target?
abstract: In our previous study, a frequent rearrangement at 4q12 has been identified by allelotyping in our large and homogeneous population of pediatric osteosarcomas and it was significantly linked to c-kit protein overexpression. To confirm and understand the involvement of KIT in this tumor, the next step of the study was designed to detect the potential mutations of KIT gene by sequencing the frequently mutated exons 6, 8, 10, 11, 13, 17 and 21 and, in case of unmutated samples, to confirm the genomic amplifications of the wild-type receptor by real-time quantitative PCR (QPCR). A new microsatellite and QPCR targeting PDGFRA was also added to check the accuracy of the 4q11-12 locus. These techniques were performed in 74 pediatric high-grade osteosarcomas treated with the OS94 protocol. Surprisingly, no mutations were found, but, only DNA amplification of KIT gene in the entire population. PDGFRA gene QPCR revealed an unexpected result of predominant deletions in the rearranged tumors. All these results confirm the major role of the 4q11-12 locus and specifically the involvement of c-kit wild-type receptor overexpression in pediatric osteosarcomas and leads us to believe that inhibitors targeting this receptor could have a therapeutic effect in a selected group of patients.
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hautepierre, 1 Avenue Molière, Strasbourg Cedex, France. natacha.entz-werle@chru-strasbourg.fr
authors.forename: Natacha
authors.initials: N
authors.lastname: Entz-Werle
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gaub
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavaux
authors.forename: Luc
authors.initials: L
authors.lastname: Marcellin
authors.forename: Nadia
authors.initials: N
authors.lastname: Metzger
authors.forename: Perrine
authors.initials: P
authors.lastname: Marec-Berard
authors.forename: Claudine
authors.initials: C
authors.lastname: Schmitt
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugiere
authors.forename: Chantal
authors.initials: C
authors.lastname: Kalifa
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Tabone
authors.forename: Hélène
authors.initials: H
authors.lastname: Pacquement
authors.forename: Philippe
authors.initials: P
authors.lastname: Gentet
authors.forename: Patrick
authors.initials: P
authors.lastname: Lutz
authors.forename: Pierre
authors.initials: P
authors.lastname: Oudet
authors.forename: Annie
authors.initials: A
authors.lastname: Babin
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D017931:DNA Primers; D005260:Female; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics*; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics
chemical_list: D017931:DNA Primers; D019009:Proto-Oncogene Proteins c-kit; D040262:Receptors, Vascular Endothelial Growth Factor