Lack of Neurofibromatosis Type 2 Gene Promoter Methylation in Sporadic Vestibular Schwannomas

Koutsimpelas, Dimitrios; Ruerup, G; Mann, Wolf J.; Brieger, Juergen

doi:10.1159/000334968

Cited by 12 publications

(9 citation statements)

References 42 publications

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“…For the rest of the cases, one might speculate on other causes of impairment of normal merlin function, including epigenetic silencing, post-translational modifications, impairment of RNA splicing, or hits in related pathways and molecules, although epigenetic silencing of NF2 does not seem to be a prevalent event. 25,26 Another issue to address is the allelic frequency by which the mutations in NF2 occur. If we use VS10 as an illustrative example, one can identify a mutation in both exons 4 and 10 with allelic fractions of 19% and 22%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Genetic landscape of sporadic vestibular schwannoma

Håvik

Bruland²,

Myrseth³

et al. 2018

Journal of Neurosurgery

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OBJECTIVE Vestibular schwannoma (VS) is a benign tumor with associated morbidities and reduced quality of life. Except for mutations in NF2, the genetic landscape of VS remains to be elucidated. Little is known about the effect of Gamma Knife radiosurgery (GKRS) on the VS genome. The aim of this study was to characterize mutations occurring in this tumor to identify new genes and signaling pathways important for the development of VS. In addition, the authors sought to evaluate whether GKRS resulted in an increase in the number of mutations. METHODS Forty-six sporadic VSs, including 8 GKRS-treated tumors and corresponding blood samples, were subjected to whole-exome sequencing and tumor-specific DNA variants were called. Pathway analysis was performed using the Ingenuity Pathway Analysis software. In addition, multiplex ligation-dependent probe amplification was performed to characterize copy number variations in the NF2 gene, and microsatellite instability testing was done to investigate for DNA replication error. RESULTS With the exception of a single sample with an aggressive phenotype that harbored a large number of mutations, most samples showed a relatively low number of mutations. A median of 14 tumor-specific mutations in each sample were identified. The GKRS-treated tumors harbored no more mutations than the rest of the group. A clustering of mutations in the cancer-related axonal guidance pathway was identified (25 patients), as well as mutations in the CDC27 (5 patients) and USP8 (3 patients) genes. Thirty-five tumors harbored mutations in NF2 and 16 tumors had 2 mutational hits. The samples without detectable NF2 mutations harbored mutations in genes that could be linked to NF2 or to NF2-related functions. None of the tumors showed microsatellite instability. CONCLUSIONS The genetic landscape of VS seems to be quite heterogeneous; however, most samples had mutations in NF2 or in genes that could be linked to NF2. The results of this study do not link GKRS to an increased number of mutations.

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Section: Discussionmentioning

confidence: 99%

Genetic landscape of sporadic vestibular schwannoma

Håvik

Bruland²,

Myrseth³

et al. 2018

Journal of Neurosurgery

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“…Contrary to non-head and neck schwannomas, sporadic vestibular schwannomas have shown no mutations on BRAF , EGFR , PIK3CA or KRAS [8]. Controversial findings on epigenetic aberrant methylation of NF2 in schwannomas have been provided [9]–[12], and data on promoter methylation of tumor-related genes have also been described [13]. The NF2 gene encodes for Merlin or Schwannomin [14], [15], a protein that shares sequence homology with members of the ezrin/radixin/moesin (ERM) family.…”

Section: Introductionmentioning

confidence: 99%

Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32

Torres‐Martín

Lassaletta²,

Campos

et al. 2013

PLoS ONE

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BackgroundVestibular schwannomas are benign tumors that arise from Schwann cells in the VIII cranial pair and usually present NF2 gene mutations and/or loss of heterozygosity on chromosome 22q. Deregulation has also been found in several genes, such as ERBB2 and NRG1. MicroRNAs are non-coding RNAs approximately 21 to 23 nucleotides in length that regulate mRNAs, usually by degradation at the post-transcriptional level.MethodsWe used microarray technology to test the deregulation of miRNAs and other non-coding RNAs present in GeneChip miRNA 1.0 (Affymetrix) over 16 vestibular schwannomas and 3 control-nerves, validating 10 of them by qRT-PCR.FindingsOur results showed the deregulation of 174 miRNAs, including miR-10b, miR-206, miR-183 and miR-204, and the upregulation of miR-431, miR-221, miR-21 and miR-720, among others. The results also showed an aberrant expression of other non-coding RNAs. We also found a general upregulation of the miRNA cluster located at chromosome 14q32.ConclusionOur results suggest that several miRNAs are involved in tumor formation and/or maintenance and that global upregulation of the 14q32 chromosomal site contains miRNAs that may represent a therapeutic target for this neoplasm.

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“…35 reported that the site-specific methylation of the promotor elements was important for NF2 silencing in sporadic VSs. However, another three studies that included 93 sporadic VSs detected no aberrant methylation of the NF2 gene in any tumours 8, 36, 37 , suggesting that promoter methylation is an uncommon mechanism of NF2 inactivation in sporadic VSs.…”

Section: Discussionmentioning

confidence: 92%

Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

Chen

Xue

Wang

et al. 2017

Sci Rep

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The great majority of sporadic vestibular schwannomas (VSs) are due to the inactivation of the NF2 gene. In this study, we found age-dependent differences in the clinical parameters of sporadic VSs. Young patients were characterized by progressive tumour behaviours, including earlier onset of initial symptoms, shorter symptom duration and larger tumour size. An increased rate of “two-hits” of both NF2 alleles, usually by mutation and allelic loss, was observed in young cases compared to older, and this correlated with the loss of protein and mRNA expression. In contrast, the tumours with a single mutation (referred to as ‘one-hit’) exhibited obvious expression levels. Moreover, a mixture of merlin-expressing tumour cells and non-expressing tumour cells was observed in ‘one-hit’ schwannomas, suggesting that a subset of ‘one-hit’ tumour cells was present in these tumours. To mimic the growth promoting effects by the second hit, we performed lentivirus-mediated NF2 knockdown in the ‘one-hit’ schwannoma cultures. Following the loss of NF2 expression, schwannoma cultures demonstrated increased proliferation rates. Above all, we have identified a correlation between the NF2 status and the growth patterns of sporadic VSs. The treatment decision-making, microsurgery or “wait and scan” strategy, should be carried out according to the tumour’s genetic background.

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Lack of Neurofibromatosis Type 2 Gene Promoter Methylation in Sporadic Vestibular Schwannomas

Cited by 12 publications

References 42 publications

Genetic landscape of sporadic vestibular schwannoma

Genetic landscape of sporadic vestibular schwannoma

Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32

Differential NF2 Gene Status in Sporadic Vestibular Schwannomas and its Prognostic Impact on Tumour Growth Patterns

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