Multi-Omic Profiling Reveals Distinct Regulatory and Epigenetic Pathways in NF2-Syndromic and Sporadic Vestibular Schwannomas

Background: Vestibular schwannomas (VS) are benign tumors of the vestibulocochlear nerve that arise either sporadically or in association with neurofibromatosis type 2 (NF2) syndrome. In both contexts, inactivation of both NF2 alleles is a central event in tumorigenesis. NF2-associated tumors, however, follow a more aggressive clinical course, with earlier onset, higher rates of progression, resistance to radiation, and worse patient outcomes. Defining the epigenetic and transcriptional differences between sporadic and NF2-associated VS may clarify mechanisms of treatment resistance and reveal potential therapeutic targets. Methods: We profiled 32 VS tumors (16 NF2-syndromic, 16 sporadic) using DNA methylation and bulk RNA sequencing, together with single-nucleus RNA/ATAC sequencing of 20,574 cells from 10 patients (6 NF2, 4 sporadic). Gene regulatory networks were reconstructed by integrating chromatin accessibility with gene expression to define enhancer-driven transcriptional programs. Results: Bulk profiling showed that NF2-associated tumors consistently exhibited promoter hypomethylation and overexpression of HOX genes, distinguishing them from sporadic tumors. Single-nucleus RNA/ATAC analysis confirmed this signature, revealing NF2-specific enrichment of HOXA9, HOXD3, and PBX1 regulatory programs. In contrast, sporadic tumors were characterized by SMAD1 activity and recurrent SMARCB1 copy number loss. Conclusion: Multi-omic profiling highlights HOX activation as a defining feature of NF2-associated VS, driven by promoter hypomethylation and enhancer-mediated regulation. Sporadic VS were instead marked by SMAD1 regulatory activity and frequent SMARCB1 loss. These findings establish distinct regulatory landscapes for NF2-associated and sporadic VS and identify HOX reactivation as a potential therapeutic vulnerability in NF2-associated disease. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany