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Pathogenese und Molekularpathologie des Vestibularisschwannoms

Pathogenesis and molecular pathology of vestibular schwannoma

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Zusammenfassung

Schwannome sind Tumoren der Nervenscheide, die sich von den Schwann-Zellen herleiten. Am häufigsten treten sie am VIII. Hirnnerv (Vestibularisschwannome) auf. Histologisch finden sich mäßig zelldichte Spindelzelltumoren mit Ausbildung von Antoni-A- und -B-Regionen sowie Verocay-Körperchen. Eine maligne Entartung ist sehr selten. Ursächlich ist die Inaktivierung von Merlin (Schwannomin), dem Genprodukt von NF2, durch Mutationen, Allelverlust oder Methylierung. Im Rahmen einer Neurofibromatose Typ 2 finden sich bei der Hälfte der Betroffenen eine Keimbahnmutation und in den Tumoren eine weitere Mutation (zweiter „hit“) des NF2-Gens. Häufig besteht ein Verlust von Chromosom 22 oder 22q. Merlin verbindet die Zellmembran mit dem Zytoskelett und reguliert intrazelluläre Signalwege, sodass der Verlust zu einer Dysorganisation des Zytoskeletts führt. Durch die Inaktivierung von Merlin werden Rac1 und Ras nicht mehr inhibiert und die Signalwege PAK1, mTORC1, EGFR-Ras-ERK, PI3K-Akt, WNT und Hippo sowie Rezeptortyrosinkinasen aktiviert. Im Zellkern inhibiert Merlin die E3-Ubiquitin-Ligase CRL4DCAF1. Neben der biallelischen Inaktivierung von NF2 in Schwannomen kommt es in Schwannomatose-assoziierten Tumoren zur Inaktivierung weiterer Gene, wie LZTR1, SMARCB1 und COQ6, wobei Erstere die Funktion des SWI/SNF-Chromatin-Remodeling-Komplexes für die Genese von Schwannomen belegen. Eigene Untersuchungen weisen auf eine Deregulierung von BAF170 hin, einer weiteren Komponente des SWI/SNF-Komplexes. Aus diesen Wirkmechanismen ergeben sich gezielte molekulare Therapieansätze, z. B. gegen mTOR (Rapamycin/Sirolmus/Everolimus), EGFR (Lapatinib) oder VEGF (Bevacizumab), obwohl klinische Studien noch keinen Anlass zur breiteren klinischen Anwendung gegeben haben.

Abstract

Schwannomas are benign Schwann cell-derived tumors of the peripheral nerve sheath often involving the vestibular cranial nerve (vestibular schwannoma). Histologically, they consist of bipolar spindle cells and show a moderate cellularity. Typically, Antoni A regions with a storiform pattern and loose Antoni B regions are intermingled. Verocay bodies are the pathognomonic palisading structures. Malignant transformation is rare. Merlin (schwannomin), the protein product of NF2, is inactivated by mutations, loss of heterozygosity or methylation. Within neurofibromatosis type 2, a germline mutation is present in about half of cases, whereas tumors demonstrate an additional second hit of the NF2 gene. A loss of chromosome 22 or 22q is common. Merlin links the cell membrane with the cytoskeleton and regulates intracellular signaling pathways leading to dysorganization when merlin is inactivated. Loss of merlin activates Rac1 and Ras, and the PAK1, mTORC1, EGFR-Ras-ERK, PI3K-Akt, WNT and Hippo pathways as well as receptor tyrosine kinases. Furthermore, merlin locates to the nucleus and inhibits E3 ubiquitin ligase CRL4DCAF1. Besides biallelic inactivation of NF2 in schwannomas, other genes are involved in the pathogenesis of schwannomatosis-associated schwannomas such as LZTR1, SMARCB1, COQ6 indicating an important role of SWI/SNF chromatin-remodeling complex for schwannoma development. Our own investigations point to deregulation of BAF170, another essential SWI/SNF complex component. Knowledge of mechanisms allows targeted molecular therapy, especially in vestibular schwannomas, using antagonists against mTOR (rapamycin/sirolmus/everolimus), EGFR (lapatinib) or VEGF (bevacizumab), although clinical studies have been in part disappointing so far.

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Danksagung

Für die Erhebungen zur Expression von Untereinheiten des SWI/SNF-Komplexes in Nervenscheidentumoren möchten wir M. Wesemann hiermit ausdrücklich danken. Dieses Teilprojekt wurde von der Innovativen Medizinischen Forschung (IMF HA121006) des Universitätsklinikums Münster gefördert.

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Authors and Affiliations

  1. Institut für Pathologie, Helios-Klinikum Erfurt, Erfurt, Deutschland

    M. Brodhun

  2. Institut für Neuropathologie, Universitätsklinikum Münster, Münster, Deutschland

    V. Stahn &  A. Harder

  3. Institut für Pathologie, Gesundheitszentrum Brandenburg an der Havel GmbH am Klinikum Brandenburg, Hochschulklinikum der Medizinischen Hochschule Brandenburg, Hochstr. 29, 14770, Brandenburg an der Havel, Deutschland

    A. Harder

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  1. M. Brodhun
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Correspondence to A. Harder.

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M. Brodhun, V. Stahn und A. Harder geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Brodhun, M., Stahn, V. & Harder, A. Pathogenese und Molekularpathologie des Vestibularisschwannoms. HNO 65, 362–372 (2017). https://doi.org/10.1007/s00106-016-0201-3

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