SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis

Abstract

BackgroundSchwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic NF2 mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the SMARCB1 (INI1) tumor suppressor gene were described in familial and sporadic schwannomatosis patients.MethodsTo delineate the SMARCB1 gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas.ResultsNine variants scattered along the sequence of SMARCB1 were identified. Five of them were classified as deleterious. All five patients carrying a SMARCB1 mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age.ConclusionsThese results suggest that patients with schwannomas have a significant probability of carrying a SMARCB1 mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the SMARCB1 gene.

Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri

“…The NF2 gene is frequently involved in the development of sporadic (non-NF2) schwannomas as well as meningiomas [8,9], and the SMARCB1 mutation in this family clearly predisposes to both sporadic tumor types. Only a limited number of other SMARCB1 mutationpositive familial (n=3) and sporadic (n=2) cases with cooccurrence of the two tumor types have been reported so far [2,3,5,10]. The reason for this low number is unclear.…”

“…The chromatin remodelling gene SMARCB1 on chromosome 22 has been identified as a predisposing gene in schwannomatosis, being involved in about 50% of familial cases but no more than 10% of sporadic cases [1][2][3][4][5]. Molecular analysis of the schwannomas of patients revealed that, in accordance with the two-hit tumor suppressor gene model, the mutant SMARCB1 allele is retained and the wild-type allele lost by loss of heterozygosity (LOH) in the tumor.…”

“…Therefore, one may wonder whether germline SMARCB1 mutations may predispose to the development of multiple meningiomas as well. The occurrence of multiple meningiomas has earlier been reported in three SMARCB1 mutation-positive schwannomatosis families [2,3,10] and recently in two sporadic schwannomatosis patients with a constitutional SMARCB1 mutation [5]. However, no data with regard to the mutational status of SMARCB1 in the meningiomas were provided in these studies.…”

Expanding the mutational spectrum of LZTR1 in schwannomatosis

“…5 However, genetic studies demonstrated that constitutional variants in this gene occur only in 40-50% of familial cases and in 8-10% of sporadic cases. [6][7][8][9] Very recently, germline variants in a novel gene, LZTR1, were identified in 100% of familial cases and in about 70% of sporadic patients. 10 LZTR1 is also located on 22q, centromeric to SMARCB1.…”

Roles of SWI/SNF Complex Genes in Breast Cancer

“…Mutations and alterations of SNF5 were also reported in familial schwannomatosis and other cancer types [75][76][77][78][79][80][81][82][83][84]. Germ line mutations of SNF5 were detected in brain tumors and rhabdoid tumors, suggesting its link with familial cancers [85][86][87][88]. In some other tumors, no alteration of SNF was detected [89,90].…”