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.

Fig. 1

Diagnostic criteria for schwannomatosis according to Ostrow et al. (2016) and Plotkin et al. (2013) based upon the criteria formulated by MacCollin et al. (2005) which predated our ability to perform molecular testing for schwannomatosis and did not consider the possibility of multiple meningiomas. a According to the findings of Castellanos et al. (2015), the deletions of 22q causing the LOH in ≥ 2 tumours should have different breakpoints for these deletions to be considered as independent events. The analysis of the extent of the LOH is necessary to exclude a large 22q deletion as the first-hit mutation (that would be identical in different tumours) which would be indicative of mosaic NF2. If an identical SMARCB1 mutation is detected in different tumours of a patient, SMARCB1-associated schwannomatosis may be diagnosed. LZTR1-associated schwannomatosis may be present, if an identical LZTR1 mutation is detected in different tumours of a patient. b High-quality MRI should include a detailed study of the internal auditory canal with slices no more than 3 mm thick. c Schwannomatosis should be considered as a possible diagnosis if two or more nonintradermal tumours are present, even if none has been pathologically confirmed to be a schwannoma; the occurrence of chronic pain in association with the tumour(s) increases the likelihood of schwannomatosis (Plotkin et al. 2013). d Smith et al. (2016) identified five patients, with unilateral vestibular schwannomas and at least two nonvestibular, nonintradermal schwannomas, who met the diagnostic criteria for NF2 but had germline LZTR1 mutations instead of germline NF2 mutations. 22q LOH: loss of heterozygosity on the long arm of chromosome 22

Fig. 2

Partial ideogram of chromosome 22 indicating the location of the LZTR1, SMARCB1, and NF2 genes and the microsatellite markers D22S420 (GenBank accession number Z23643.1), D22S1174 (GenBank acc. No. Z51327.1), and D22S1148 (GenBank acc. No. Z52647.1). The nucleotide numbering is given according to hg19. Linkage analysis provided the original evidence that the schwannomatosis predisposition genes are located within the ~8.5-Mb region between markers D22S420 and D22S1148 (MacCollin et al. 2003). The centromeric direction is on the left side, the telomeric direction is on the right side of the schema

Fig. 3

Models of tumorigenesis in schwannomatosis. a Four-hit/3-step model in patients with an heterozygous germline SMARCB1 mutation (first hit and step). The second step includes loss of heterozygosity (LOH) of 22q which removes the wild-type SMARCB1 allele and one of the two NF2 alleles. The third step is the somatic mutation of the other NF2 allele located on the chromosome harbouring the germline SMARCB1 mutation. b Four-hit/3-step model of tumorigenesis in patients with an heterozygous germline LZTR1 mutation (first hit and step). c Five-hit/3-step model of tumorigenesis in schwannomatosis. The LOH event which removes one wild-type LZTR1 allele and one copy of NF2 automatically leads to the loss of one SMARCB1 allele, which represents the fifth mutational hit

Fig. 4

Estimation of the relative proportions of familial and sporadic patients with germline mutations in LZTR1 or SMARCB1 among patients who fulfil the clinical diagnostic criteria for schwannomatosis. These estimates are derived from studies of individuals diagnosed with schwannomatosis according to clinical diagnostic criteria without preselection for those patients who have been shown to harbour different somatic NF2 gene mutations in at least two different schwannomas (Boyd et al. ; Hadfield et al. ; Sestini et al. ; Rousseau et al. ; Hutter et al. ; Smith et al. 2012b, 2014, 2015)

Fig. 5

Comprehensive mutation analysis of all three genes, LZTR1, SMARCB1, and NF2, in patients with schwannomatosis should be performed to identify the complete mutational spectra and the number of mutational hits that affect these genes. This comprehensive testing may help to classify the tumours according to their mutation-profile. The mutation analysis should also include methods, such as next-generation sequencing, which are well suited to detect somatic mosaicism with mutant cells present in low proportions. This approach should identify tumour heterogeneity and help to distinguish between mosaic NF2 and schwannomatosis, since some NF2 patients with somatic mosaicism for an NF2 gene mutation fulfil the diagnostic criteria for schwannomatosis (Plotkin et al. 2013)