Abstract
Objective: To elucidate the genetic etiology of sporadic vestibular schwannomas (VSs) and investigate the correlation between NF2 inactivation mechanisms and preoperative clinical characteristics, including hearing function and tumor growth. Methods: Nineteen patients who underwent VS resection at our otorhinolaryngology or neurosurgery department between June 2020 and March 2022 were included in this study. Whole-exome sequencing (WES) was performed to detect somatic changes in NF2. Additionally, NF2 promoter methylation status and copy number changes were evaluated using methylation analysis and multiple ligation-dependent probe amplification (MLPA). Preoperative clinical data, including pure tone audiometry, speech discrimination scores, and tumor growth rates, were collected and analyzed for correlations with genetic findings. Results: WES identified somatic alterations in both NF2 alleles in 16 cases (84.2%). The addition of methylation analysis and MLPA confirmed biallelic NF2 inactivation in all cases. NF2 promoter methylation was suggested to be associated with hearing loss and tumor progression. A weak correlation between NF2 expression levels and tumor growth rate was observed (r = 0.21), while no significant correlation was found between NF2 expression and pure tone audiometry or speech discrimination scores. Conclusion: Comprehensive genetic analyses, including WES, methylation analysis, and MLPA, are essential for identifying NF2 inactivation mechanisms in sporadic VSs. The findings suggest that NF2 methylation may contribute to variations in clinical presentation. Further studies with larger cohorts are necessary to clarify the role of epigenetic modifications in disease progression and their potential impact on patient management strategies. Level of evidence: 4.