Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas

• Published in: Journal of medical genetics Vol. 48; no. 2; pp. 93 - 97
• Main Authors: Christiaans, I, Kenter, S B, Brink, H C, van Os, T A M, Baas, F, van den Munckhof, P, Kidd, A M J, Hulsebos, T J M
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.02.2011; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Age; Base Sequence; Biological and medical sciences; Cardiovascular disease; Chromosomal Proteins, Non-Histone - genetics; DNA Mutational Analysis; DNA Primers - genetics; DNA-Binding Proteins - genetics; Epilepsy; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes, Neurofibromatosis 2; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Germ-Line Mutation - genetics; Humans; Male; Medical genetics; Medical sciences; Meningioma - genetics; Meningioma - pathology; Microsatellite Repeats - genetics; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; neuro oncology; Neurology; Patients; Pedigree; SMARCB1 Protein; Spinal cord; Surgery; Transcription Factors - genetics; Tumors; Tumors of the nervous system. Phacomatoses; Twins; Human; Somatic mutation; Nervous system diseases; Multiple; Family study; Germ line; Genetics; Benign neoplasm; Meningioma; Molecular genetics; Neuro oncology
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2010.082420

BackgroundMultiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated.ResultsFive affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele.ConclusionIt is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.