The Molecular Genetics of Schwannomatosis

Theo JM Hulsebos, Academic Medical Center, Amsterdam, The Netherlands

Published online: March 2009

DOI: 10.1002/9780470015902.a0021427

Schwannomatosis is characterized by the development of multiple schwannomas, but without the involvement of vestibular schwannomas. Presence of the latter is the hallmark of neurofibromatosis type 2 (NF2). Recent studies in families with schwannomatosis have excluded the NF2 gene on chromosome 22 as the germline-transmissible schwannomatosis gene. However, this gene was found to be somatically inactivated in schwannomas of the patients. In 2007, the INI1/SMARCB1 gene on chromosome 22 was identified as a strong candidate for the schwannomatosis-predisposing gene. Subsequent studies have confirmed the involvement of this tumour suppressor gene in 40–50% of familial and about 10% of sporadic cases. INI1/SMARCB1 had earlier been found to be implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. It remains to be explained how INI1/SMARCB1 can be involved in the development of benign schwannomas and of malignant rhabdoid tumours as well.

Key concepts

  • Schwannomatosis is characterized by the development of multiple schwannomas but no vestibular schwannomas, which are diagnostic of neurofibromatosis type 2 (NF2).
  • INI1/SMARCB1 on chromosome 22 is a schwannomatosis-predisposing gene. Constitutional mutations in this gene are found in 40–50% of familial cases and about 10% of sporadic cases.
  • INI1/SMARCB1 is a tumour suppressor gene of which the second wild-type copy is found to be inactivated in the schwannomas of these patients.
  • Inactivating mutations in the NF2 gene are also found in the schwannomas of schwannomatosis patients, but these are only somatically acquired.
  • The INI1/SMARCB1 protein is a core subunit of the SWI/SNF complex. The SWI/SNF complex is involved in chromatin-remodelling and in cancer development.
  • INI1/SMARCB1 is also implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. Patients with rhabdoid tumour predisposition syndrome (RTPS) carry a constitutionally mutated INI1/SMARCB1 gene and may develop more than one rhabdoid tumour.
  • It remains to be clarified how INI1/SMARCB1 can be involved in the development of two tumour types, schwannomas and rhabdoid tumours, with very different histologies and malignancy grades.

Keywords: schwannomatosis; schwannoma; rhabdoid tumour; INI1/SMARCB1; NF2

Figure 1. Immunohistochemical INI1/SMARCB1 staining of a schwannoma derived from a schwannomatosis patient with a constitutional INI1/SMARCB1 mutation (c.34C>T p.Q12X, panel a), and of a malignant rhabdoid tumour derived from a rhabdoid tumour predisposition syndrome patient with a constitutional INI1/SMARCB1 mutation (c.500+1G>A p.W167X, panel b). Note mosaic nuclear staining of tumour cells in the schwannoma and absence of nuclear staining in the tumour cells of the malignant rhabdoid tumour. In contrast, the nuclei of endothelial cells of the blood vessels in both tumours show positive staining with the INI1/SMARCB1 antibody. Original magnification ×200. Panel a, reproduced from Hulsebos et al. (2007) with permission from Elsevier. Panel b, reproduced from Ammerlaan et al. (2008), with permission from British Journal of Cancer.
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Related Sub-Topics:

Neurobiology of Disease | Glia | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Cancer Genetics | Gene Mapping by Disease Association | Transcriptional Regulation
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Article Title: The Molecular Genetics of Schwannomatosis
 
How to Cite close
Hulsebos, Theo JM(Mar 2009) The Molecular Genetics of Schwannomatosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021427]