CpG island hypermethylation of the neurofibromatosis type 2 (NF2) gene is rare in sporadic vestibular schwannomas

Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Neuropathology and Applied Neurobiology (Impact Factor: 3.93). 10/2010; 36(6):505-14. DOI: 10.1111/j.1365-2990.2010.01090.x
Source: PubMed


Loss of both wild-type copies of the neurofibromatosis type 2 (NF2) gene is found in both sporadic and neurofibromatosis type 2-associated vestibular schwannomas (VS). Previous studies have identified a subset of VS with no loss or mutation of NF2. We hypothesized that methylation of NF2 resulting in gene silencing may play a role in such tumours.
Forty sporadic VS were analysed by array comparative genomic hybridization using 1 Mb whole genome and chromosome 22 tile path arrays. The NF2 genes were sequenced and methylation of NF2 examined by pyrosequencing.
Monosomy 22 was the only recurrent change found. Twelve tumours had NF2 mutations. Eight tumours had complete loss of wild-type NF2, four had one mutated and one wild-type allele, 11 had only one wild-type allele and 17 showed no abnormalities. Methylation analysis showed low-level methylation in four tumours at a limited number of CpGs. No high-level methylation was found.
This study shows that a significant proportion of sporadic VS (>40%) have unmethylated wild-type NF2 genes. This indicates that other mechanisms, yet to be identified, are operative in the oncogenesis of these VSs.

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    • "Thus, methylation seems to play an important role in processes related to myelin formation in schwannomas, possibly exhibiting epigenetic changes leading to dedifferentiation. Based on our data, the NF2 gene does not seem to be affected by methylation processes in schwannomas, in agreement with Koutsimpelas et al., (2012) and Lee et al., (2012), although methylation in a small subset of samples should not be ruled out (Gonzalez-Gomez et al., 2003; Kullar et al., 2010). Additionally, the NF1 gene, which is involved in neurofibromatosis Type 1 (NF1) syndrome, contains a small gene within an intron named EVI2A. "
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    ABSTRACT: Schwannomas are tumors that develop from Schwann cells in the peripheral nerves and commonly arise from the vestibular nerve. Vestibular schwannomas can present unilaterally and sporadically or bilaterally when the tumor is associated with neurofibromatosis Type 2 (NF2) syndrome. The molecular hallmark of the disease is biallelic inactivation of the NF2 gene. The epigenetic signature of schwannomas remains poorly understood and is mostly limited to DNA methylation of the NF2 gene, whose altered expression due to epigenetic factors in this tumor is controversial. In this study, we tested the genomewide DNA methylation pattern of schwannomas to shed light on this epigenetic alteration in these particular tumors. The methodology used includes Infinium Human Methylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 nonvestibular schwannomas, and 5 healthy nerves. Our results show a trend toward hypomethylation in schwannomas. Furthermore, homeobox (HOX) genes, located at four clusters in the genome, displayed hypomethylation in several CpG sites in the vestibular schwannomas but not in the nonvestibular schwannomas. Several microRNA (miRNA) and protein-coding genes were also found to be hypomethylated at promoter regions and were confirmed as upregulated by expression analysis; including miRNA-21, Met Proto-Oncogene (MET), and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP, which would increase the complexity of the methylation and expression patterns. Overall, our results show specific epigenetic signatures in several coding genes and miRNAs that could potentially be used as therapeutic targets. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · Genes Chromosomes and Cancer
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    • "Another study confirmed NF2 promoter methylation as a frequent event in schwannomas although at a much lower rate [46]. More recently, it was determined that there were a significant number of sporadic vestibular schwannoma patients that did not exhibit methylation of wild-type NF2 (>40%) [47]. Given the discrepancy regarding NF2 methylation in schwannomas, several studies aimed to determine the methylation status in other tumors of the nervous system such as meningiomas and ependymomas. "
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    ABSTRACT: Neurofibromatosis type 2 (NF2), characterized by tumors of the nervous system, is a result of functional loss of the NF2 gene. The NF2 gene encodes Merlin (moesin-ezrin-radixin-like protein), an ERM (Ezrin, Radixin, Moesin) protein family member. Merlin functions as a tumor suppressor through impacting mechanisms related to proliferation, apoptosis, survival, motility, adhesion, and invasion. Several studies have summarized the tumor intrinsic mutations in Merlin. Given the fact that tumor cells are not in isolation, but rather in an intricate, mutually sustaining synergy with their surrounding stroma, the dialog between the tumor cells and the stroma can potentially impact the molecular homeostasis and promote evolution of the malignant phenotype. This review summarizes the epigenetic modifications, transcript stability, and post-translational modifications that impact Merlin. We have reviewed the role of extrinsic factors originating from the tumor milieu that influence the availability of Merlin inside the cell. Information regarding Merlin regulation could lead to novel therapeutics by stabilizing Merlin protein in tumors that have reduced Merlin protein expression without displaying any NF2 genetic alterations.
    Full-text · Article · Jun 2012 · Biochimica et Biophysica Acta
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    • "Lomas et al. [20] proposed that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas. However, Kullar et al. [21] recently reported that hypermethylation of the CpG island of the NF2 gene was rare in sporadic vestibular schwannomas. None of our patients showed repressed expression of the NF2 gene due to hypermethylation of the promoter region. "
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    ABSTRACT: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.
    Preview · Article · Jan 2012 · PLoS ONE
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