Document Detail

Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.
MedLine Citation:
PMID:  16461335     Owner:  NLM     Status:  MEDLINE    
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.
Ophélia Maertens; Hans Prenen; Maria Debiec-Rychter; Agnieszka Wozniak; Raf Sciot; Patrick Pauwels; Ivo De Wever; Joris R Vermeesch; Thomas de Raedt; Anne De Paepe; Frank Speleman; Allan van Oosterom; Ludwine Messiaen; Eric Legius
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-02-06
Journal Detail:
Title:  Human molecular genetics     Volume:  15     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-01     Completed Date:  2007-11-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1015-23     Citation Subset:  IM    
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
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MeSH Terms
Carcinoid Tumor / genetics
DNA Mutational Analysis
Duodenal Neoplasms / genetics
Gastrointestinal Stromal Tumors / etiology*,  genetics*
Middle Aged
Neurofibromatosis 1 / etiology*,  genetics*
Neurofibromin 1 / genetics
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-kit / genetics
Receptor, Platelet-Derived Growth Factor alpha / genetics
Tumor Cells, Cultured
Reg. No./Substance:
0/Neurofibromin 1; EC Proteins c-kit; EC, Platelet-Derived Growth Factor alpha

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