Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.
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.
Maertens
Ophélia
O
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Prenen
Hans
H
Debiec-Rychter
Maria
M
Wozniak
Agnieszka
A
Sciot
Raf
R
Pauwels
Patrick
P
De Wever
Ivo
I
Vermeesch
Joris R
JR
de Raedt
Thomas
T
De Paepe
Anne
A
Speleman
Frank
F
van Oosterom
Allan
A
Messiaen
Ludwine
L
Legius
Eric
E
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
D025542:Neurofibromin 1; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha