Differential Methylation Profiling Reveals Distinct Pathways in NF2 Syndromic and Sporadic Vestibular Schwannomas
Bibliographic record
Abstract
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 germ line 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. Semisupervised clustering methods were employed to define differentially methylated probes between the two groups ([ Fig. 1A,B ]). Additional subgroup analysis was conducted comparing solid and cystic tumors within the sporadic VS group ([ Fig. 2 ]). Gene pathway enrichment analysis was inferred from the hypo- and hyper-methylated genes ([ Fig. 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. Publication History Article published online: 07 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".