The Molecular Genetics of Schwannomatosis

Abstract

Schwannomatosis is characterized by the development of multiple schwannomas, but without the involvement of vestibular schwannomas. Presence of the latter is the hallmark of neurofibromatosis type 2 (NF2). Recent studies in families with schwannomatosis have excluded the NF2 gene on chromosome 22 as the germline‐transmissible schwannomatosis gene. However, this gene was found to be somatically inactivated in schwannomas of the patients. In 2007, the INI1/SMARCB1 gene on chromosome 22 was identified as a strong candidate for the schwannomatosis‐predisposing gene. Subsequent studies have confirmed the involvement of this tumour suppressor gene in 40–50% of familial and about 10% of sporadic cases. INI1/SMARCB1 had earlier been found to be implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. It remains to be explained how INI1/SMARCB1 can be involved in the development of benign schwannomas and of malignant rhabdoid tumours as well. Key concepts Schwannomatosis is characterized by the development of multiple schwannomas but no vestibular schwannomas, which are diagnostic of neurofibromatosis type 2 (NF2). INI1/SMARCB1 on chromosome 22 is a schwannomatosis‐predisposing gene. Constitutional mutations in this gene are found in 40–50% of familial cases and about 10% of sporadic cases. INI1/SMARCB1 is a tumour suppressor gene of which the second wild‐type copy is found to be inactivated in the schwannomas of these patients. Inactivating mutations in the NF2 gene are also found in the schwannomas of schwannomatosis patients, but these are only somatically acquired. The INI1/SMARCB1 protein is a core subunit of the SWI/SNF complex. The SWI/SNF complex is involved in chromatin‐remodelling and in cancer development. INI1/SMARCB1 is also implicated in the development of malignant rhabdoid tumours, which are aggressive tumours of early childhood. Patients with rhabdoid tumour predisposition syndrome (RTPS) carry a constitutionally mutated INI1/SMARCB1 gene and may develop more than one rhabdoid tumour. It remains to be clarified how INI1/SMARCB1 can be involved in the development of two tumour types, schwannomas and rhabdoid tumours, with very different histologies and malignancy grades.

SMARCB1/INI1 maternal germ line mosaicism in schwannomatosis

“…Although little is known about the function of the various parts of the SMARCB1 protein, one may speculate that the deletion has only a moderate effect on its function. Splice site and missense mutations are the predominant types of mutation found in the SMARCB1 gene of schwannomatosis patients (14). Furthermore, we could show the presence of independent and somatically acquired truncating NF2 mutations in three schwannomas of patient II-2 and their absence in the constitutional DNA of this patient and of patient II-1, which are also typical features of schwannomatosis patients (10)(11)(12)(15)(16)(17).…”