Human Molecular Genetics Advance Access originally published online on February 6, 2006
Human Molecular Genetics 2006 15(6):1015-1023; doi:10.1093/hmg/ddl016
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Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients
1Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 2Department of Clinical Oncology, 3Department of Human Genetics, 4Department of Pathology and 5Oncological Surgery, Catholic University Leuven, Leuven, Belgium, 6Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland, 7Department of Pathology, University Hospital Maastricht, Maastricht, The Netherlands and 8Department of Genetics, University of Alabama, Birmingham, AL, USA
* To whom correspondence should be addressed at: Department of Human Genetics, Catholic University Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345903; Fax: +32 16346051; Email: eric.legius{at}uz.kuleuven.ac.be
Received October 24, 2005; Revised January 18, 2006; Accepted February 1, 2006
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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