Abstract
BackgroundMutations 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.Methodology/Principal Findings 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.Conclusions/SignificanceThe 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.
Highlights
Vestibular schwannomas (VS) are benign tumors of the neural sheath that originate on the vestibular nerves
Six of the eight frameshift mutations resulted in the premature termination of translation and the other two frameshift mutations generated a truncated protein via exon skipping caused by the loss of a splice acceptor or donor site
This study investigated the genetic alterations in sporadic vestibular schwannomas (VS), including mutations, loss of heterozygosity (LOH), and epigenetic alterations of the neurofibromatosis type 2 (NF2) gene, and compared these alterations with the tumor behavior
Summary
Vestibular schwannomas (VS) are benign tumors of the neural sheath that originate on the vestibular nerves They occur as either sporadic unilateral tumors or bilateral tumors that are a manifestation of neurofibromatosis type 2 (NF2). The loss of both wild-type copies of the NF2 tumor suppressor gene is common in the pathogenesis of both sporadic and NF2-related schwannomas [1,2]. The importance of DNA methylation in tumors has been acknowledged, and the hypermethylation of promoterassociated CpG islands is emerging as the primary mechanism of epigenetic inactivation of tumor-suppressor genes in cancer development [3,4]. 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
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