Carcinogenesis Advance Access published online on December 15, 2005
Carcinogenesis, doi:10.1093/carcin/bgi273
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1 Institute of Neuropathology, Charité - Universitätsmedizin Berlin, Germany
* To whom correspondence should be addressed. Platelet-derived growth factor receptor alpha (PDGFR
Received September 20, 2005
Revised November 3, 2005
Accepted November 12, 2005
CARCINOGENESIS
PDGFRA and KIT dysregulation and mutation in malignant peripheral nerve sheath tumours
Nikola Holtkamp 1 *,
Ali Fuat Okuducu 1,
Jana Mucha 1,
Anastasia Afanasieva 1,
Christian Hartmann 1,
Isis Atallah 1,
Lope Estevez-Schwarz 2,
Christian Mawrin 3,
Reinhard E. Friedrich 4,
Victor-F. Mautner 4,
and
Andreas von Deimling 1
2 Department of Surgery and Surgical Oncology, Robert-Rössle-Hospital, Berlin, Germany
3 Department of Neuropathology, Otto-von-Guericke-University, Magdeburg, Germany
4 Department of Oral and Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany
Nikola Holtkamp, E-mail: nikola.holtkamp{at}charite.de
Abstract 
) and c-Kit are receptor tyrosine kinases. Both are targets of the tyrosine kinase inhibitor imatinib mesylate which is approved for treatment of some cancers. In order to assess the role of PDGFR and c-Kit in malignant peripheral nerve sheath tumours (MPNST) we examined human tumours for structural alterations, protein and ligand expression. We investigated 34 MPNST, 6 corresponding plexiform neurofibromas and 1 MPNST cell culture from 31 patients for mutations and polymorphisms in PDGFRA (exon 2-21) and KIT (exon 9, 11, 13, 17). PDGFRA was amplified in 7 tumours from 6 patients and MPNST cell culture S462. KIT was amplified in 5 tumours from 4 patients and in the cell culture. Two MPNST carried somatic PDGFRA mutations in exons coding for the extracellular domain. In addition we detected several polymorphisms in PDGFRA. No point mutations or polymorphisms were detected in the 4 KIT exons analysed. PDGFR expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFR ligands in MPNST and neurofibromas revealed that PDGF-A was more widely expressed than PDGF-B. Focal c-Kit expression was detected in 2 of 29 (7%) MPNST patients. Imatinib treatment of MPNST cell culture S462 exerted a growth inhibitory effect and prevented PDGF-AA induced PDGFR phosphorylation. In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib.
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