Immunohistochemical Analysis Supports a Role for INI1/SMARCB1 in Hereditary Forms of Schwannomas, but Not in Solitary, Sporadic Schwannomas

Abstract

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis 1 . Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares to other multiple schwannoma syndromes (sporadic schwannomatosis and neurofibromatosis 2) as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.The SMARCB1 (also known as INI1, hSNF5 and BAF47) is a tumor suppressor gene that maps to chromosome band 22q11.2. Biallelic inactivation of SMARCB1 is frequent in atypical teratoid/rhabdoid tumors (AT/RT) and malignant rhabdoid tumors, aggressive malignant tumors of the central nervous system and kidneys in children. Constitutional mutations of SMARCB1 can be seen in rare familial cases of AT/RT 2 . The protein encoded by SMARCB, the INI1 protein, is a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex and is ubiquitously expressed in all cell types examined 3 . AT/RT occurring both sporadically SMARCB1 lies in the candidate region for familial schwannomatosis, a form of neurofibromatosis characterized by multiple schwannomas without vestibular nerve involvement 5,6 . In a recent report 1 , constitutional and somatic mutations of the SMARCB1gene were found in tumors from a single kindred with familial schwannomatosis. Loss of nuclear INI1 protein expression by immunohistochemistry was seen in four separate tumors from two members of this family. However, in contrast to the immunostaining pattern of INI1 in AT/ RT, loss of INI1 expression was seen in only a subset of tumor cells suggesting a mosaic makeup of null and haploinsufficent cells. Furthermore, several previous studies have identified somatically acquired mutations in the NF2 gene in schwannomatosis tumors 6 ,, 7 , but in tumors from this family no molecular evidence of NF2 involvement was seen, raising the question of how representative this family may be. Here we report an expansion of these results to other familial schwannomatosis kindreds as well as analysis of the INI expression pattern in tumors associated with other multiple schwannoma syndromes (sporadic schwannomatos...

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.…”

Recent developments in brain tumor predisposing syndromes

“…Although schwannomatosis patients lack NF2 germline mutation, the interaction between these two genes and disorders are complex and not fully understood. Mosaic SMARCB1 expression has been reported in 83% of NF2-related schwannomas [48]. Furthermore, virtually all SMARCB1-schwannomatosis-related schwannomas have somatic NF2 mutations [49].…”

Intracerebral schwannomas: a rare disease with varying natural history

“…In a series of cases of familial schwannomatosis and NF2-associated schwannomas, INI1 immunohistochemistry showed zonal loss of expression, providing evidence of a role for this gene in some types of hereditary schwannoma. 37 In our case, and in 1 previously reported intracerebral MPNST in a patient with NF1, there was diffuse immunoreactivity for INI1, suggesting that INI1/SMARCB1 mutations may not be involved in NF1-associated NSTs. 2 This series of 3 cases allows for contrast of the pathological features of conventional intracerebral schwannomas, seen in Cases 2 and 3, with the much less common and potentially more aggressive cellular schwannoma, as typified by Case 1.…”

“…37 The INI1 immunohistochemical reactivity is lost in atypical teratoid/rhabdoid tumors due to mutations in the INI1/ SMARCB1 tumor suppressor gene. In most normal tissues and in tumors not associated with the INI1/SMARCB1 mutation there is diffuse nuclear immunoreactivity.…”