Journal Article

Mutation and expression of <i>PDGFRA</i> and <i>KIT</i> in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity

Nikola Holtkamp, Ali Fuat Okuducu, Jana Mucha, Anastasia Afanasieva, Christian Hartmann, Isis Atallah, Lope Estevez-Schwarz, Christian Mawrin, Reinhard E. Friedrich, Victor-F. Mautner and Andreas von Deimling

in Carcinogenesis

Volume 27, issue 3, pages 664-671
Published in print March 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi273
Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

Platelet-derived growth factor receptor alpha (PDGFRα) 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 PDGFRα 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 (pNF) 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 seven tumours from six patients and MPNST cell culture S462. KIT was amplified in five tumours from four 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 four KIT exons analysed. PDGFRα expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRα 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 PDGFRα 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.

Keywords: DMSO, dimethylsulfoxide; GIST, gastrointestinal stromal tumours; MPNST, malignant peripheral nerve sheath tumours; NF1, neurofibromatosis type 1; PDGFRα, platelet-derived growth factor receptor alpha; pNF, plexiform neurofibromas

Journal Article.  5237 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.