Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas
Résumé
Background Multiple meningiomas occur in less than 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. Results We investigated five affected members of a large family with multiple meningiomas for the presence of mutations in SMARCB1 and NF2. We identified a missense mutation in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas and 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, we identified independent somatically acquired NF2 mutations in two meningiomas of one patient with concomitant losses of the wild-type NF2-allele. Conclusion We conclude 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.
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