Meningiomas are, in general, slowly growing benign tumors derived from the arachnoidal cap cells of the leptomeninges, the soft coverings of the brain and spinal cord. Meningiomas are believed to be the most common primary tumors of the ... Meningiomas are, in general, slowly growing benign tumors derived from the arachnoidal cap cells of the leptomeninges, the soft coverings of the brain and spinal cord. Meningiomas are believed to be the most common primary tumors of the central nervous system in man. The vast majority of meningiomas are sporadic; familial occurrence of meningioma is rare (Zang, 2001). Familial or multiple meningiomas may also be seen in tumor predisposition syndromes. Some patients with schwannomatosis (162091), caused by mutation in the SMARCB1 gene, may develop meningiomas. One patient with malignant gliomas (GLM2; 613028) associated with a mutation in the PTEN gene (601728) developed a meningioma (Staal et al., 2002).
Aavikko et al. (2012) reported a Finnish family in which 5 sibs had adult-onset meningiomas between the ages of 43 and 72 years. Four of the 5 had multiple tumors. Germline and somatic alterations of the NF2 gene ... Aavikko et al. (2012) reported a Finnish family in which 5 sibs had adult-onset meningiomas between the ages of 43 and 72 years. Four of the 5 had multiple tumors. Germline and somatic alterations of the NF2 gene were excluded in these patients. No mutation carriers had medulloblastoma. Smith et al. (2013) reported 6 patients from 4 unrelated families with spinal meningiomas. The age at onset was between 15 and 30 years, and 5 of the patients were female. Three of the woman developed the tumors during pregnancy, suggesting a hormonal influence on penetrance. All tumors showed a clear-cell histology.
In affected members of a Finnish family with multiple adult-onset meningiomas, Aavikko et al. (2012) identified a germline heterozygous mutation in the SUFU gene (R123C; 607035.0007). The mutation was identified ... - Mutation in the SUFU Gene In affected members of a Finnish family with multiple adult-onset meningiomas, Aavikko et al. (2012) identified a germline heterozygous mutation in the SUFU gene (R123C; 607035.0007). The mutation was identified by genomewide linkage analysis combined with exome sequencing. Tumor tissue from 7 meningiomas showed loss of heterozygosity at the SUFU locus, consistent with a 2-hit model for tumor suppressor genes. In vitro functional expression studies in human rhabdomyosarcoma cells showed that the R123C mutant protein had a significantly decreased ability to suppress GLI1 (165220) activity compared to wildtype SUFU, resulting in aberrant activation of the hedgehog signaling pathway. SUFU mutations were not identified in 162 additional Finnish patients with meningioma. - PDGFB Gene Bolger et al. (1985) reported 2 living sibs with meningioma who were found to have a variant of the SIS oncogene (PDGFB; 190040) on chromosome 22q12 in peripheral leukocyte DNA. Family studies showed that the SIS variant segregated with the normal chromosome 22. Later studies by Smidt et al. (1990) showed that the affected members of the family reported by Bolger et al. (1985) had deletion of Alu sequences in the fifth intron of the SIS gene (190040.0001). - MN1 Disruption Lekanne Deprez et al. (1995) used a balanced translocation involving chromosome 22 from a meningioma to isolate a gene they designated MN1 (156100) which was disrupted by the translocation. In the meningioma carrying this translocation, no expression of the MN1 mRNA was observed. The translocation in this case represented a germline change in a patient with multiple meningiomas (Lekanne Deprez et al., 1991). - SMARCB1 Gene Bacci et al. (2010) reported a family in which affected individuals had multiple schwannomas and meningiomas associated with a heterozygous mutation in the SMARCB1 gene (E31V; 601607.0010). Bacci et al. (2010) noted that meningiomas are not frequently found in patients with schwannomatosis (162091), but should be considered part of the phenotype. Christiaans et al. (2011) reported a family in which 5 individuals developed meningiomas, 2 of whom also developed schwannomas. All patients carried a heterozygous mutation in the SMARCB1 gene (P48L; 601607.0011), and meningioma tumors showed loss of the wildtype allele, consistent with the 2-hit hypothesis of tumorigenesis. Meningiomas developed between ages 34 and 56 years, both in the cranium as extra-axial lesions and in the spinal cord as extramedullary lesions. In addition, 1 patient developed multiple chest wall and spinal schwannomas and another developed a single vestibular schwannoma. Two different meningioma tumors from the same patient also carried 2 different heterozygous somatic mutations in the NF2 gene (607379) as well as loss of heterozygosity at the NF2 locus. Christiaans et al. (2011) concluded that the SMARCB1 mutation predisposed the carriers to the development of meningiomas. The mutation may also have predisposed carriers to schwannomas, implying that meningiomas may be part of the schwannomatosis tumor spectrum, as suggested by Bacci et al. (2010), but the schwannomas may also be coincidental findings. The role of the NF2 mutations was uncertain, but may contribute to a 4-hit hypothesis involving 2 genes. Van den Munckhof et al. (2012) provided further studies of the family reported by Christiaans et al. (2011). Reexamination of tumor tissue from 4 meningiomas and 2 schwannomas showed that all tumors had LOH for both SMARCB1 and NF2, consistent with a deletion of a segment of chromosome 22 containing these 2 genes. Three meningiomas and 2 schwannomas were each found to carry somatic mutations in the NF2 gene. Thus, the genetic changes found in the 2 tumor types were the same and characteristic for SMARCB1-mutation positive tumors: retention of the exon 2 mutation, acquisition of an NF2 mutation, and LOH of the wildtype allele of both genes. In addition, van den Munckhof et al. (2012) identified 11 more carriers of the P48L mutation in this family. Eight of these 11 mutation carriers were found to carry 11 lesions suggestive of cranial meningioma and 6 spinal lesions consistent with meningiomas or schwannomas. Nine (82%) of the 11 cranial meningiomas were found in the falx cerebri. Van den Munckhof et al. (2012) concluded that meningiomas should be included in the schwannomatosis tumor spectrum. - SMARCE1 Gene In 6 patients from 4 unrelated families with spinal meningiomas, Smith et al. (2013) identified 4 different heterozygous loss-of-function mutations in the SMARCE1 gene (603111.0002-603111.0005). The first 2 mutations were identified by exome sequencing, and the second 2 were found by Sanger sequencing of the SMARCE1 gene in 6 additional patients with spinal meningiomas. One unaffected father was heterozygous for the mutation, indicating incomplete penetrance. All spinal tumors were clear-cell type, and all tumors studied showed loss of the SMARCE1 protein, consistent with a tumor suppressor mechanism. However, only 1 of 3 tumors analyzed showed loss of heterozygosity for wildtype SMARCE1. Sequencing SMARCE1 in 34 individuals with multiple cranial meningiomas did not identify any mutations, suggesting that the mutations are specific for spinal tumors. Smith et al. (2013) postulated that loss of SMARCE1 activity may lead to the uncoupling of apoptotic control. - Associations Pending Confirmation Dobbins et al. (2011) performed a genomewide association study of 859 affected individuals with meningioma and 704 controls with validation in 2 independent sample sets totaling 774 cases and 1,764 controls. They identified a new susceptibility locus for meningioma at 10p12.31 in the MLLT10 gene (602409) at dbSNP rs11012732 (odds ratio = 1.46, combined P value = 1.88 x 10(-14)). - Somatic Mutations In 8 of 70 sporadic meningiomas, Peyrard et al. (1994) found specific loss of expression of a beta-adaptin gene called BAM22 (600157). They reviewed the evidence suggesting that multiple genes on chromosome 22 are involved in the oncogenesis of meningioma and suggested that BAM22 may be second in importance to the NF2 gene. Wellenreuther et al. (1995) suggested that the NF2 gene represents the meningioma locus on chromosome 22. The association of LOH on chromosome 22 with somatic mutations in the NF2 gene was significant. Somatic NF2 mutations occurred significantly more frequently in fibroblastic meningioma (70%) and transitional meningioma (83%) than in meningiothelial meningioma (25%), thus indicating a differential molecular pathogenesis of these meningioma variants. Schmitz et al. (2001) found the same somatic mutation in exon 9 of the SMARCB1 gene (arg377-to-his; R377H) in 4 of 126 meningiomas. The data indicated that SMARCB1 is a candidate tumor suppressor gene on chromosome 22 that may be important for the genesis of meningiomas. Eckstein et al. (2004) reported a 42-year-old man with a single meningioma that was resected. Over the next 15 years, he developed multiple recurrent meningiomas with the same histopathology in different areas of the brain, spinal cord, and lung. He had no clinical history of NF2 or vestibular schwannomas and no family history of meningioma. Genetic analysis of all tumor DNA identified a somatic 2-bp deletion in exon 1 of the NF2 gene, which was not present in the patient's blood. The second NF2 allele was lost in the tumors, consistent with the action of NF2 as a tumor suppressor gene. Eckstein et al. (2004) noted the unusual recurrence, long survival, and lack of histologic progression of the tumor over a long period of time and postulated that other genes may be involved.