Molecular predictors of recurrence in vestibular schwannomas: a transcriptomic and RT-qPCR analysis

PURPOSE: Vestibular schwannomas (VS) are benign tumors with variable clinical behavior. Recurrence after surgery is uncommon yet sometimes aggressive. Reliable molecular predictors of recurrence are lacking, and the correlation between genotype and phenotype is weak. This study aimed to identify molecular markers associated with recurrence in VS and explore their prognostic potential. METHODS: Retrospective case-control study of patients undergoing VS surgery between 2017 and 2024. RNA-Seq was conducted to identify molecular signatures associated with recurrence, and selected genes were validated using RT-qPCR. Recurrence-free and salvage surgery-free survival were analyzed by the extent of resection. RESULTS: 23 samples from 22 patients were analyzed, including 7 recurrent and 16 non-recurrent cases. 81 differentially expressed genes were identified in recurrent tumors, with enrichment of the MAPK (FDR = 7.9 × 10⁻⁴) and PI3K/AKT/mTOR (FDR = 0.038) pathways. Eight candidate genes were selected for validation: DCN (FC 4.34); DUSP5 (FC 4.20); CXCL8 (FC 3.25); JUND (FC 3.27); MYC (FC 2.45); MAFF (FC 3.79); SOD3 (FC 2.47) (all upregulated), and TNF (FC 0.16) (downregulated). RT-qPCR confirmed that CXCL8 and TNF were significantly elevated in tumors requiring early salvage surgery and in an NF2-associated Schwannomatosis case. No differences in recurrence-free or salvage surgery-free survival were observed between near-total and subtotal resections. CONCLUSION: Recurrent VS exhibit a distinct molecular profile, highlighting IL-8 and TNFα as potential biomarkers and therapeutic targets. These findings support the development of a prognostic panel to guide personalized follow-up and treatment, particularly for high-risk patients. Further studies are needed before clinical implementation.