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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: 4.97). 10/2010; 36(6):505-14. DOI: 10.1111/j.1365-2990.2010.01090.x
Source: PubMed

ABSTRACT 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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    • "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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