Methylation Profiling Reveals Subgroups of Intracranial Schwannoma with Distinct Biological and Clinical Features

Background: Intracranial schwannomas, most commonly affecting the vestibular nerve, are associated with clinical heterogeneity despite universal categorization as grade 1 by the World Health Organization based on histopathology. We have previously demonstrated that vestibular schwannomas (VS) can be represented by two molecular groups: “immunogenic,” with increased immune infiltration, and “proliferative,” with relatively more neoplastic cells. The purpose of this follow up study was to validate the biological relevance of these molecular groups using a larger de novo cohort while also exploring their translation value for clinical practice. Methods: Methylation profiling was performed on paraffin embedded tissue (Illumina EPICv2) and used to classify cases into molecular groups, identify chromosome-level copy number gains/losses (conumee), and infer tumor purity using the established Leukocyte UnMethylated for Purity (LUMP) score. Clinical variables including syndromic neurofibromatosis (NF2) status, preoperative Koos grade, age, sex, and nerve of origin were collected for each case. Results: Out cohort included 351 intracranial schwannomas ( n = 309 VS, 42 schwannomas of other cranial nerves) resected at the University of Tubingen. Ninety-two (26%) classified as immunogenic and 259 (74.8%) as proliferative. Inferred tumor purity (LUMP score) was significantly higher in the proliferative group ( p < 0.001) and correlated strongly with the first principal component loadings of the 10,000 most variably methylated probes (r = 0.93, p < 0.001), demonstrating that tumor microenvironment (represented by molecular groups) is a major driver of overall biological heterogeneity. The proportion of non-VS cases was higher in immunogenic than proliferative cases (17/92 [18.5%] versus 25/259 [9.7%], p = 0.04). Proliferative cases were more commonly associated with chromosome 22q loss (124/259 [47.9%] versus 17/92 [18.5%], p < 0.001), suggesting differences in the distribution of driver events between molecular groups. Among VS, immunogenic tumors were associated with higher Koos grade on average ( p = 0.007) and were more likely to have had previous RT (9/75 [12.0%] versus 6/233[2.6%], p = 0.003), suggesting a more aggressive and radioresistant phenotype. No differences were observed in neurofibromatosis status, age, or sex between molecular groups. Conclusion: We validate the biological relevance two molecular subgroups of intracranial schwannoma, “immunogenic” and “proliferative,” using the largest cohort of intracranial schwannoma to date generated specifically for the purpose of this study. We demonstrate that chromosome 22q loss is more common in proliferative cases, suggesting differences in tumorigenesis between groups, and that immunogenic VS are larger and more radioresistant, suggesting more aggressive behavior. This highlights the need for targeted immune-based therapy for a subset of such tumors which recur despite surgery and radiotherapy. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany