Involvement of SMARCB1 in Inherited Predisposition to Schwannoma, Meningioma and Rhabdoid Tumours

Abstract

Meningiomas are benign tumors of the meninges and make up one third of all primary CNS tumors in adults. Schwannomas are benign nerve sheath tumors that can occur on nearly all nerves but are most predominant on the vestibular nerve. Around 1 in 300 people develop a symptomatic meningioma in their lifetime and 1 in 500 develop a schwannoma. Rarely both meningiomas and schwannomas occur at multiple sites, usually occurring in patients with neurofibromatosis 2 (NF2). NF2 accounts for around 3-5% of all cases of schwannoma and 2-3% of people with meningiomas. However, not all multiple site cases are accounted for by NF2 germline mutations. The SWI/SNF chromatin remodeling complex gene, SMARCB1, is a cause of schwannomatosis disease. SMARCB1 mutations account for around ∼50% of familial cases of schwannomatosis and ∼10% of sporadic cases. We have identified SMARCB1 germline mutations in 14/31 (45%) families with multiple affected individuals and 15/123 (12%) sporadic cases. The presumed pathogenic 3’ untranslated region mutation c.*82C>T was found in 6 families. Many schwannomatosis related SMARCB1 mutations occurred in extreme ends of the gene and were presumed hypomorphic. Meningiomas occur rarely in schwannomatosis disease (only in 2/55 individuals with SMARCB1 mutations). Sequencing of SMARCB1 in 37 cases of multiple cranial meningiomas and 14 cases of spinal meningioma (5 familial) failed to identify any germline mutations. We will also present data on germline testing of around 100 cases of malignant rhabdoid tumour.