Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri

Neurogenetics. 2012 Feb;13(1):1-7. doi: 10.1007/s10048-011-0300-y. Epub 2011 Oct 26.

Abstract

Schwannomatosis is a rare hereditary cancer syndrome in which patients develop multiple non-vestibular schwannomas. The chromatin remodelling gene SMARCB1 (also known as INI1, hSNF5, and BAF47) has been identified as a schwannomatosis predisposing gene, being involved in a subset of sporadic and familial cases. Recent studies have shown that SMARCB1 may also be involved in the development of multiple meningiomas. Previously, we demonstrated that the SMARCB1 exon 2 missense mutation c.143 C > T segregates with the presence of meningiomas in five members of a large family with multiple meningiomas and schwannomas. We extended our genetic analyses by screening 44 additional at-risk family members and identified 13 new carriers. Eleven of these were subjected to magnetic resonance imaging (MRI) of brain and spine. In addition, we analyzed four meningiomas and two schwannomas from family members for the presence of schwannomatosis-specific changes. We found in each tumor retention of the SMARCB1 exon 2 mutation, acquisition of an independent neurofibromatosis type 2 (NF2) gene mutation, and loss of heterozygosity at SMARCB1 and NF2 by loss of the wild-type copy of both genes. The MRI scans revealed one or more falx meningiomas in seven of 11 (64%) newly identified SMARCB1 mutation carriers. We conclude that the SMARCB1 exon 2 missense mutation in this family predisposes to the development of meningiomas as well as schwannomas, occurring via the same genetic pathways, and that this mutation preferentially induces cranial meningiomas located at the falx cerebri.

MeSH terms

  • Adult
  • Aged
  • Base Sequence
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Dura Mater / pathology*
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Germ-Line Mutation*
  • Humans
  • Male
  • Meningeal Neoplasms / genetics*
  • Meningeal Neoplasms / pathology
  • Meningioma / genetics*
  • Meningioma / pathology
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense
  • Neurilemmoma / genetics*
  • Neurilemmoma / pathology
  • Pedigree
  • SMARCB1 Protein
  • Transcription Factors / genetics*
  • Young Adult

Substances

  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors