title: Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Ophélia
authors.initials: O
authors.lastname: Maertens
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.forename: Ivo
authors.initials: I
authors.lastname: De Wever
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.forename: Thomas
authors.initials: T
authors.lastname: de Raedt
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Allan
authors.initials: A
authors.lastname: van Oosterom
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D000328:Adult; D000368:Aged; D002276:Carcinoid Tumor / Q000235:genetics; D004252:DNA Mutational Analysis; D004379:Duodenal Neoplasms / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000209:etiology* / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D025542:Neurofibromin 1; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha