2025 Proffered Presentations
S089: DIFFERENTIAL METHYLATION PROFILING REVEALS DISTINCT PATHWAYS IN NF2-SYNDROMIC AND SPORADIC VESTIBULAR SCHWANNOMAS
Yosef Ellenbogen, MD; Alex Landry, MD; Suganth Suppiah, MD, PhD, FRCSC; Gelareh Zadeh, MD, PhD, FRCSC; University of Toronto
Introduction: Vestibular schwannomas (VS) are the most common tumors in the cerebellopontine angle and represent one of the most challenging skull base tumors to treat. VS arise from the vestibular division of cranial nerve VIII within the internal acoustic canal. These tumors develop sporadically in 90% of cases, with the remainder occurring in the context of hereditary tumor predisposition syndromes such as neurofibromatosis type 2 (NF2). NF2 mutations play a key role in the development of both sporadic and NF2-related VS. Heterozygous germline inactivating mutations of NF2 lead to the clinical syndrome of NF2, while biallelic somatic mutations of NF2 are seen in the majority of sporadic VS. Understanding the epigenetic divergence between NF2 and sporadic VS may inform additional therapies, particularly for NF2 VS, which pose significant treatment challenges.
Methods: Thirty-two VS tumors (16 NF2-syndromic and 16 sporadic) were identified and profiled using DNA methylation and RNA sequencing. Semi-supervised clustering methods were employed to define differentially methylated probes between the two groups (Figure 1A,B). Additional subgroup analysis was conducted comparing solid and cystic tumors within the sporadic VS group (figure 2). Gene pathway enrichment analysis was inferred from the hypo- and hyper-methylated genes (Figure 1C.
Results: Analysis of differentially methylated pathways revealed that NF2 VS had hypomethylated promoter regions associated with extracellular matrix and immune evasion pathways, suggesting a potentially more robust immunomodulatory environment. In contrast, sporadic VS had hypomethylated promoter regions related to metabolic pathways, including glycosaminoglycan biosynthesis and cholesterol metabolism. Additionally, methylation-based LUMP (leukocytes unmethylation to infer tumor purity) scores indicated lower tumor purity in cystic compared to solid tumors.
Conclusion: DNA methylation analysis revealed unique differentially methylated pathways between NF2 and sporadic VS. Further validation with RNA sequencing and in vitro assays will help identify potential therapeutic vulnerabilities for NF2-associated VS.
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