The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

Abstract

Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite the clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis is not caused by germline NF2 gene mutations. Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. In contrast to patients with rhabdoid tumours, which are due to complete loss-of-function SMARCB1 mutations, individuals with schwannomatosis harbour predominantly hypomorphic SMARCB1 mutations which give rise to the synthesis of mutant proteins with residual function that do not cause rhabdoid tumours. Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. This review provides an overview of current models of tumorigenesis and mutational patterns underlying schwannomatosis that will ultimately help to explain the complex clinical presentation of this rare disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1753-8) contains supplementary material, which is available to authorized users.

Distinctive low epidermal nerve fiber density in schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis

“…Genetically, NF2 patients exhibit germline mutations in the NF2 gene while a majority of schwannomatosis patients have germline mutations in the SMARCB1 or LZTR1 genes , all located on chromosome 22q. However, the two disorders share common somatic alterations in associated tumors which is the biallelic inactivation of the NF2 gene.…”

SWI/SNF-Komplex-assoziierte Tumordispositions-Syndrome

“…Die Schwannomatose ist selten, ihre Häufigkeit wird auf 1:40.000-1:70.000 geschätzt. Schwannomatose tritt meist sporadisch auf, 13-25 % der Fälle sind familiär (zusammengefasst in [18] …”

“…Es ist jedoch zu berücksichtigen, dass die genetische Ursache der Schwannomatose bei etwa 60 % dersporadischenund 14 % derfamiliären Fälle derzeit ungeklärt bleibt. Die disponierenden Gene bei Patienten ohne Keimbahnmutationen in LZTR1 oder SMARCB1 sind bislang noch nicht bekannt (zusammengefasst in [18] …”

“…Auch etwa die Hälfte der Patienten mit NF2 entwickelt Meningeome, aber nur bei 4 % der NF2-Patienten treten diese multipel auf [32]. Bei Patienten mit Keimbahnmutationen in SMARCB1 sind multiple Meningeome bei gleichzeitig auftretenden Schwannomen beobachtet worden (Übersicht in [18] …”

Co‐occurrence of schwannomatosis and rhabdoid tumor predisposition syndrome 1

“…Genetic heterogeneity is observed in schwannomatosis since germline mutations in LZTR1 have also been identified in patients with the disease (Hutter et al, 2014;Louvrier et al, 2018;Paganini et al, 2015;Piotrowski et al, 2012;Smith et al, 2015). Furthermore schwannomatosis predisposition genes are likely to exist since germline mutations in SMARCB1 or LZTR1 are not detectable in at least 50% of sporadic patients with schwannomatosis (Kehrer-Sawatzki, Farschtschi, Mautner, & Cooper, 2017). However, the frequency of somatic mosaicism of SMARCB1 or LZTR1 mutations in patients with schwannomatosis is as yet unclear.…”