Human Molecular Genetics Advance Access published online on February 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl016
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1 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
* To whom correspondence should be addressed. 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. In order 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 (1) the NF1-related GISTs do not have KIT or PDGFRA mutations, (2) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (3) 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 to sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of gastrointestinal stromal tumors in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
Received October 24, 2005
Revised January 18, 2006
Accepted February 1, 2006
Article
Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients
Ophélia Maertens 1,
Hans Prenen 2,
Maria Debiec-Rychter 3,
Agnieszka Wozniak 4,
Raf Sciot 5,
Patrick Pauwels 6,
Ivo De Wever 7,
Joris R. Vermeesch 3,
Thomas de Raedt 3,
Anne De Paepe 1,
Frank Speleman 1,
Allan van Oosterom 2,
Ludwine Messiaen 8,
and
Eric Legius 9 *
2 Department of Clinical Oncology, Catholic University Leuven, Leuven, Belgium
3 Department of Human Genetics, Catholic University Leuven, Leuven, Belgium
4 Department of Human Genetics, Catholic University Leuven, Leuven, Belgium; Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland
5 Department of Pathology, Catholic University Leuven, Leuven, Belgium
6 Department of Pathology, University Hospital Maastricht, Maastricht, The Netherlands
7 Oncological Surgery, Catholic University Leuven, Leuven, Belgium
8 Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Genetics, University of Alabama, Birmingham, United States
9 Department of Human Genetics, Catholic University Leuven, Herestraat 49, B-3000, Leuven, Belgium
Eric Legius, E-mail: Eric.Legius{at}uz.kuleuven.ac.be
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