Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis

Abstract

Schwannomatosis is a third major form of neurofibromatosis that has recently been linked to mutations in the SMARCB1 (hSnf5/INI1) tumor suppressor gene. We analyzed the coding region of SMARCB1 by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) in genomic DNA from 19 schwannomatosis kindreds. Microsatellite markers in the SMARCB1 region were developed to determine loss of heterozygosity (LOH) in associated tumors. We detected four alterations in conserved splice acceptor or donor sequences of exons 3, 4 and 6. Two alterations that likely affect splicing were seen in introns 4 and 5. An additional four alterations of unclear pathogenicity were found to segregate on the affected allele in eight families including two non-conservative missense alterations in three families. No constitutional deletions or duplications were detected by MLPA. Nine of 13 tumors examined showed partial LOH of the SMARCB1 region consistent with 'second hits.' Alterations were detected in tumors both with and without somatic NF2 gene changes. These findings support the hypothesis that SMARCB1 is a tumor suppressor for schwannomas in the context of familial disease. Further work is needed to determine its role in other multiple and single tumor syndromes.

Incidence of atypical teratoid/rhabdoid tumors in children

“…Alterations of the SMARCB1 gene have recently been implicated in several other tumors, such as epithelioid sarcomas, single cases of gangliogliomas, familial schwannomas, and cribriform neuroepithelial tumors. 37,[44][45][46][47][48][49] These findings indicate that the morphology needs to be cautiously interpreted in conjunction with the immunohistochemical profile for the differential diagnosis of atypical teratoid/ rhabdoid tumors. Indeed, 2 tumors in our series displayed features of epithelioid sarcoma and showed loss of SMARCB1 protein expression.…”

Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas

“…In SMARCB1-positive schwannomatosis, the initiating event is a germline SMARCB1 mutation with the second proposed event being an LOH deletion of 22q that removes the wild-type SMARCB1 and an allelic copy of NF2 (Hulsebos et al, 2007;Boyd et al, 2008;Hadfield et al, 2008;Sestini et al, 2008). The third hit would be an NF2 mutation on the remaining ipsilateral allele to the germline SMARCB1 mutation.…”

“…The chromatin remodelling gene, SMARCB1, located approximately 6 Mb upstream of NF2 at 22q11.23, was recently found to be mutated in germline DNA in approximately 50% of familial schwannomatosis patients, and, less commonly, in sporadic schwannomatosis (5-10%) (Hulsebos et al, 2007;Boyd et al, 2008;Hadfield et al, 2008;Sestini et al, 2008). Our previous study has shown that these germline SMARCB1 mutations are frequently associated with a somatic NF2 mutation in tumours (Boyd et al, 2008;Hadfield et al, 2008), and a multihit hypothesis has been suggested, involving both of these loci (Boyd et al, 2008;Hadfield et al, 2008;Sestini et al, 2008).…”

“…Our previous study has shown that these germline SMARCB1 mutations are frequently associated with a somatic NF2 mutation in tumours (Boyd et al, 2008;Hadfield et al, 2008), and a multihit hypothesis has been suggested, involving both of these loci (Boyd et al, 2008;Hadfield et al, 2008;Sestini et al, 2008).…”

Empirical development of improved diagnostic criteria for neurofibromatosis 2

“…11,12 Schwannomatosis has been defined as a distinct clinical entity, 9 excluded from the NF2 locus, 30 and shown to be related to mutations of the SMARCB1 locus in some patients. [31][32][33][34] Most importantly, we have begun to understand the molecular pathogenesis of NF2, 1,[35][36][37] and this is permitting the development of novel therapeutic initiatives. 25,38 -41 Both NF2 and other conditions with which it may be confused clinically are being recognized more frequently, 42 probably because of the availability of high-quality MRI.…”