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Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors

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Abstract

Neurofibromas represent one of the hallmarks of neurofibromatosis 1 (NF1) patients. Tumor progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNST) is a frequent and life threatening complication. To learn more about processes involved in malignant transformation, we evaluated differential gene expression in plexiform neurofibroma and MPNST from the same NF1 patient. Suppression subtractive hybridization (SSH) yielded 133 differentially expressed genes confirmed by reverse Northern blotting. Virtual Northern blots were employed to validate 23 genes. To independently verify differential expression, immunohistochemical analyses with antibodies to matrix metalloproteinase 13 (MMP13), platelet-derived growth factor receptor alpha (PDGFRA) and fibronectin (FN1) were performed on 9 dermal and 9 plexiform neurofibromas and 16 MPNST from 19 NF1 patients. All three proteins proved to be up-regulated in MPNST. MMP13 expression was observed in 44% of MPNST but was absent in neurofibromas. PDGFRA was expressed in all tumors, but the number of cells expressing it was below 30% in neurofibromas and over 50% in MPNST. Likewise, FN1 was expressed in all tumors, but less than 30% of the cells in neurofibromas and more than 70% of the cells in MPNST exhibited antibody binding. Our data point to several genes not previously recognized to be differentially expressed, and provide a framework for future studies on progression-associated gene expression in low- and high-grade nerve sheath tumors.

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Acknowledgements

We thank Kathrein Stichling for her technical assistance and Dr. Michael Baier and Prof. Reinhold Schäfer for helpful discussions. This work was supported by the Deutsche Krebshilfe.

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Authors and Affiliations

  1. Institute of Neuropathology, Charité, Humboldt University, Campus Virchow Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany

    Nikola Holtkamp, Anja Harder, Christian Hartmann, Agota Theallier-Janko & Andreas von Deimling

  2. Department of Neurology, Klinikum North Ochsenzoll General Hospital, 22419, Hamburg, Germany

    Victor-F. Mautner

  3. Department of Oral and Maxillofacial Surgery, Eppendorf University Hospital, University of Hamburg, 20246, Hamburg, Germany

    Reinhard E. Friedrich

  4. Department of Radiology, Charité, Humboldt University, , 13353, Berlin, Germany

    Karl T. Hoffmann

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  1. Nikola Holtkamp
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Correspondence to Andreas von Deimling.

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Holtkamp, N., Mautner, VF., Friedrich, R.E. et al. Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors. Acta Neuropathol 107, 159–168 (2004). https://doi.org/10.1007/s00401-003-0797-8

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  • DOI: https://doi.org/10.1007/s00401-003-0797-8

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