Molecular Genetics of Schwannomatosis

Abstract

Schwannomatosis is characterised by the development of multiple schwannomas, and in some cases meningiomas, but without the involvement of bilateral vestibular schwannomas, the latter being the hallmark of neurofibromatosis type 2 (NF2). Severe pain is the most important clinical symptom in patients. Germ line mutations in SMARCB1 or LZTR1 on chromosome 22 predispose to the development of schwannomas in schwannomatosis. These genes explain 86% of the familial but only 40% of the sporadic cases. Independent somatic mutations in NF2, which is also on chromosome 22, are found in the schwannomas of patients, but not in their germ line. Most mutations in SMARCB1 are hypomorphic mutations, giving rise to a SMARCB1 protein with modified activity. Many mutations in LZTR1 are loss‐of‐function mutations, resulting in the absence of LZTR1 protein. Unilateral vestibular schwannomas may occur in LZTR1‐associated schwannomatosis. Overlap exists of the clinical symptoms of schwannomatosis and mosaic NF2. Comprehensive testing of the genes involved in blood and tumours of the patient may help in the clinical diagnosis of schwannomatosis. Identification of additional genes and pathways involved should be performed to identify possible targets for therapy and relief of pain.

Key Concepts

  • Schwannomatosis patients develop multiple schwannomatosis, but not bilateral vestibular schwannomas, the latter being characteristic for neurofibromatosis type 2 (NF2).
  • Pain is the most important clinical symptom in schwannomatosis. It often persists after removal of the schwannoma.
  • The tumour suppressor genes SMARCB1 and LZTR1 are predisposing genes in schwannomatosis. These genes explain many, but not all, sporadic and familial cases.
  • Most germ line SMARCB1 mutations in schwannomatosis are hypomorphic mutations, resulting in the synthesis of a protein with modified activity.
  • Many germ line LZTR1 mutations are loss‐of‐function mutations, resulting in the absence of protein.
  • Independent somatically acquired NF2 mutations are found in the multiple schwannomas of schwannomatosis patients.
  • Unilateral vestibular schwannoma may occur in LZTR1‐associated schwannomatosis. Bilateral vestibular schwannomas have not been reported in schwannomatosis patients.
  • The similarities in clinical phenotype between schwannomatosis and mosaic NF2 may cause diagnostic confusion.

Keywords: schwannomatosis; rhabdoid tumour; vestibular schwannoma; SMARCB1; LZTR1; NF2; tumour suppressor gene; mutation

Figure 1. Immunohistochemical SMARCB1 staining of a schwannoma derived from a schwannomatosis patient with a constitutional SMARCB1 mutation (c.34C > T; p.Gln12*, a) and of a malignant rhabdoid tumour derived from a rhabdoid tumour predisposition syndrome patient with a constitutional SMARCB1 mutation (c.500+1G > A; p.Trp167*, 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 SMARCB1 antibody. Original magnification ×200. (a) Reproduced from Hulsebos et al. 2007 © Elsevier. (b) Reproduced with permission from Ammerlaan et al. 2008 © Nature Publishing Group.
Figure 2. Four‐hit, three‐step mechanism for SMARCB1 and NF2 inactivation in multiple schwannomas of a SMARCB1 mutation‐positive schwannomatosis patient. Tumorigenesis begins with a germ line mutation in SMARCB1 (hit 1) and is followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3) and by mutation of the remaining wild‐type NF2 allele (hit 4). Reproduced with permission from Plotkin et al. 2013 © John Wiley and Sons.
Figure 3. Nucleotide sequence of the coding region in exon 1 of SMARCB1 and amino acid sequence of the encoded N‐terminal part of the SMARCB1 protein. Nucleotide numbering starts at the A of the first ATG codon and amino acid numbering starts at the first methionine. The nucleotides that are affected by the c.30delC, c.34C > T, c.38delA and c.46A > T mutations are indicated in red colour, as are the premature termination codon TGA at position 44, generated by the c.30delC and c.38delA mutations, and the possible reinitiation codon ATG at position 79. The c.79A > G mutation, introduced to convert the latter codon into GTG, encoding valine, is also indicated (see text for details). Reproduced with permission from Hulsebos et al. 2014b © Springer.
close

References

Ammerlaan AC, Ararou A, Houben MP, et al. (2008) Long‐term survival and transmission of INI1‐mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome. British Journal of Cancer 98: 474–479.

Bacci C, Sestini R, Provenzano A, et al. (2010) Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics 11: 73–80.

Betz BL, Strobeck MW, Reisman DN, et al. (2002) Re‐expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1 arrest associated with induction of p16ink4a and activation of RB. Oncogene 21: 5193–5203.

Boyd C, Smith MJ, Kluwe L, et al. (2008) Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clinical Genetics 74: 358–366.

Caltabiano R, Magro G, Polizzi A, et al. (2017) A mosaic pattern of INI1/SMARCB1 protein expression distinguishes schwannomatosis and NF2‐associated peripheral schwannomas from solitary peripheral schwannomas and NF2‐associated vestibular schwannomas. Childs Nervous System 33 (6): 933–940. DOI: 10.1007/s00381-017-3340-2. [Epub ahead of print] PubMed PMID: 28365909.

Carter JM, O'Hara C, Dundas G, et al. (2012) Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with “neuroblastoma‐like” schwannomatosis and a novel germline SMARCB1 mutation. American Journal of Surgical Pathology 36: 154–160.

Christiaans I, Kenter SB, Brink HC, et al. (2011) Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. Journal of Medical Genetics 48: 93–97.

Eaton KW, Tooke LS, Wainwright LM, et al. (2011) Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatric Blood & Cancer 56: 7–15.

Frattini V, Trifonov V, Chan JM, et al. (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nature Genetics 45: 1141–1149.

Geller JI, Roth JJ and Biegel JA (2015) Biology and treatment of rhabdoid tumor. Critical Reviews in Oncogenesis 20: 199–216.

Graham RP, Dry S, Li X, et al. (2011) Ossifying fibromyxoid tumor of soft parts: a clinicopathologic, proteomic, and genomic study. American Journal of Surgical Pathology 35: 1615–1625.

Hadfield KD, Newman WG, Bowers NL, et al. (2008) Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. Journal of Medical Genetics 45: 332–339.

Hadfield KD, Smith MJ, Urquhart JE, et al. (2010) Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene 29: 6216–6221.

Hulsebos TJ, Plomp AS, Wolterman RA, et al. (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. American Journal of Human Genetics 80: 805–810.

Hulsebos TJ, Kenter S, Siebers‐Renelt U, et al. (2014a) SMARCB1 involvement in the development of leiomyoma in a patient with schwannomatosis. American Journal of Surgical Pathology 2014 (38): 421–425.

Hulsebos TJ, Kenter S, Verhagen WI, et al. (2014b) Premature termination of SMARCB1 translation may be followed by reinitiation in schwannomatosis‐associated schwannomas, but results in absence of SMARCB1 expression in rhabdoid tumors. Acta Neuropathologica 128: 439–448.

Hulsebos TJ, Kenter S, Baas F, et al. (2016) Type 1 papillary renal cell carcinoma in a patient with schwannomatosis: mosaic versus loss of SMARCB1 expression in respectively schwannoma and renal tumor cells. Genes, Chromosomes & Cancer 55: 350–354.

Hutter S, Piro RM, Reuss DE, et al. (2014) Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants. Acta Neuropathologica 128: 449–452.

Jacoby LB, Jones D, Davis K, et al. (1997) Molecular analysis of the NF2 tumor‐suppressor gene in schwannomatosis. American Journal of Human Genetics 61: 1293–1302.

Jagani Z, Mora‐Blanco EL, Sansam CG, et al. (2010) Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog‐Gli pathway. Nature Medicine 16: 1429–1433.

Janson K, Nedzi LA, David O, et al. (2006) Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatric Blood & Cancer 47: 279–284.

Kalpana GV, Marmon S, Wang W, et al. (1994) Binding and stimulation of HIV‐1 integrase by a human homolog of yeast transcription factor SNF5. Science 266: 2002–2006.

Kaufman DL, Heinrich BS, Willett C, et al. (2003) Somatic instability of the NF2 gene in schwannomatosis. Archives of Neurology 60: 1317–1320.

Kehrer‐Sawatzki H, Wolf S, Lichter P, et al. (2017) The molecular pathogenesis of schwannomatosis, a paradigm for the co‐involvement of multiple tumour suppressor genes in tumorigenesis. Human Genetics 136: 129–148.

Koontz NA, Wiens AL, Agarwal A, et al. (2013) Schwannomatosis: the overlooked neurofibromatosis? American Journal of Roentgenology 200: W646–W653.

MacCollin M, Woodfin W, Kronn D and Short MP (1996) Schwannomatosis: a clinical and pathologic study. Neurology 46: 1072–1079.

MacCollin M, Willett C, Heinrich B, et al. (2003) Familial schwannomatosis: exclusion of the NF2 locus as the germline event. Neurology 60: 1968–1974.

Merker VL, Esparza S, Smith MJ, et al. (2012) Clinical features of schwannomatosis: a retrospective analysis of 87 patients. The Oncologist 17: 1317–1322.

Mora‐Blanco EL, Mishina Y, Tillman EJ, et al. (2014) Activation of b‐catenin/TCF targets following loss of the tumor suppressor SNF5. Oncogene 33: 933–938.

van den Munckhof P, Christiaans I, Kenter SB, et al. (2012) Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. Neurogenetics 13: 1–7.

Ostrow KL, Donaldson K, Blakeley J, et al. (2015) Immortalized human Schwann cell lines derived from tumors of schwannomatosis patients. PLoS One 10: e0144620.

Paganini I, Chang VY, Capone GL, et al. (2015a) Expanding the mutational spectrum of LZTR1 in schwannomatosis. European Journal of Human Genetics 23: 963–968.

Paganini I, Sestini R, Cacciatore M, et al. (2015b) Broadening the spectrum of SMARCB1‐associated malignant tumors: a case of uterine leiomyosarcoma in a patient with schwannomatosis. Human Pathology 46: 1226–1231.

Patil S, Perry A, MacCollin M, et al. (2008) Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathology 18: 517–519.

Piotrowski A, Xie J, Liu YF, et al. (2014) Germline loss‐of‐function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nature Genetics 46: 182–187.

Plotkin SR, Blakeley JO, Evans DG, et al. (2013) Update from the 2011 international schwannomatosis workshop: from genetics to diagnostic criteria. American Journal of Medical Genetics. Part A 161A: 405–416.

Schneppenheim R, Frühwald MC, Gesk S, et al. (2010) Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. American Journal of Human Genetics 86: 279–284.

Sestini R, Bacci C, Provenzano A, et al. (2008) Evidence of a four‐hit mechanism involving SMARCB1 and NF2 in schwannomatosis‐associated schwannomas. Human Mutation 29: 227–231.

Sévenet N, Sheridan E, Amram D, et al. (1999) Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. American Journal of Human Genetics 65: 1342–1348.

Smith MJ, Wallace AJ, Bowers NL, et al. (2012a) Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 13: 141–145.

Smith MJ, Walker JA, Shen Y, et al. (2012b) Expression of SMARCB1 (INI1) mutations in familial schwannomatosis. Human Molecular Genetics 21: 5239–5245.

Smith MJ, Isidor B, Beetz C, et al. (2015) Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 84: 141–147.

Smith MJ, Bowers NL, Bulman M, et al. (2017) Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1‐related schwannomatosis. Neurology 88: 87–92.

Swensen JJ, Keyser J, Coffin CM, et al. (2009) Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. Journal of Medical Genetics 46: 68–72.

Taylor MD, Gokgoz N, Andrulis IL, et al. (2000) Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. American Journal of Human Genetics 66: 1403–1406.

Val‐Bernal JF, Mayorga M and Sedano‐Tous MJ (2013) Schwannomatosis presenting as pancreatic and submandibular gland schwannoma. Pathology, Research and Practice 12: 817–822.

Versteege I, Sévenet N, Lange J, et al. (1998) Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394: 203–206.

Wilson BG and Roberts CW (2011) SWI/SNF nucleosome remodellers and cancer. Nature Reviews Cancer 11: 481–492.

Yamamoto H, Kohashi K, Tsuneyoshi M, et al. (2011) Heterozygosity loss at 22q and lack of INI1 gene mutation in gastrointestinal stromal tumor. Pathobiology 78: 132–139.

Zhang K, Lin JW, Wang J, et al. (2014) A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis. Genetics in Medicine 16: 787–792.

Further Reading

Allen MD, Freund SM, Zinzalla G and Bycroft M (2015) The SWI/SNF subunit INI1 contains an N‐terminal winged helix DNA binding domain that is a target for mutations in schwannomatosis. Structure 23: 1344–1349.

Farschtschi S, Mautner VF, Pham M, et al. (2016) Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. Annals of Neurology 80: 625–628.

Gossai N, Biegel JA, Messiaen L, et al. (2015) Report of a patient with a constitutional missense mutation in SMARCB1, Coffin‐Siris phenotype, and schwannomatosis. American Journal of Medical Genetics. Part A 167A: 3186–3191.

Kadoch C, Williams RT, Calarco JP, et al. (2017) Dynamics of BAF‐Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nature Genetics 49: 213–222.

Smith MJ, O'Sullivan J, Bhaskar SS, et al. (2013) Loss‐of‐function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nature Genetics 45: 295–298.

Smith MJ (2015) Germline and somatic mutations in meningiomas. Cancer Genetics 208: 107–114.

Tsurusaki Y, Okamoto N, Ohashi H, et al. (2012) Mutations affecting components of the SWI/SNF complex cause Coffin‐Siris syndrome. Nature Genetics 44: 376–378.

Wang X, Lee RS, Alver BH, et al. (2017) SMARCB1‐mediated SWI/SNF complex function is essential for enhancer regulation. Nature Genetics 49: 289–295.

Yamamoto GL, Aguena M, Gos M, et al. (2015) Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. Journal of Medical Genetics 52: 413–421.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hulsebos, Theo JM(Nov 2017) Molecular Genetics of Schwannomatosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021427.pub2]