Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas

Imke Christiaans (1) , Susan Kenter (2) , Helmy Brink (1) , Theo van Os (1) , Frank Baas (2) , Pepijn van den Munckhof (3) , Alexa Kidd (4) , Theo Hulsebos (2)

1 Dept Clinical Genetics, AMC, Amsterdam
2 Dept Neurogenetics, AMC, Amsterdam
3 Dept Neurosurgery, AMC, Amsterdam
4 Canterbury Health Laboratories, Christchurch

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.

Mots clés: Molecular genetics; Neuro oncology

Imke Christiaans, Susan Kenter, Helmy Brink, Theo van Os, Frank Baas, et al.. Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. Journal of Medical Genetics, 2010, 48 (2), pp.93. ⟨10.1136/jmg.2010.082420⟩. ⟨hal-00573999⟩