Dysregulated Genes and Biologic Pathway Analysis in Early versus Late Recurrences of Sporadic Vestibular Schwannomas

Background: Vestibular Schwannomas (VS) are slow-growing, benign tumors that arise from the myelin-producing Schwann cells of the vestibular branch of CN VIII. Though benign, these tumors carry significant morbidity, primarily due to their close association with important nerves. They are usually sporadic and unilateral and comprise 8% of all intracranial tumors. The role of genetic and epigenetic alterations in sporadic VS is not well established. The current gold standard of treatment for these tumors is total surgical resection, though radiotherapy is also efficacious. Recurrence in patients undergoing subtotal resection (STR) approaches 90%, while recurrence with gross total resection (GTR) is >15% on follow-up >10 years. Previous surgical series examining sporadic VS have discussed recurrence risks through surgical, histological, and immunohistochemical perspectives. However, there is a paucity of literature focusing on the genetic mechanisms involved in the recurrence of schwannomas.

Objective: In this study, we use RNA-sequencing data to identify gene expression differences in early and late recurrences of VS and further identify the pathways associated with tumor recurrence. We aim to identify genes and their biologic pathways associated with recurrences in vestibular schwannomas.

Methods: We reviewed 20 patients surgically treated for CN VIII schwannomas in the 10-year period between 2005 and 2015 at our institution. Biopsies of their tumors were sequenced using an RNA-sequencing platform. Patient demographics, tumor characteristics, treatment modalities, pathologic data, and patient performance data were collected. Differential expression analysis of RNA-sequencing data was performed using EdgeR and DeSeq2 programs to determine the significant gene expression changes in our cohort of early versus late recurrences. The significant upregulated and downregulated genes were then matched for biologic pathways involved using REACTOME pathway analyzer.

Results: Our patients were predominantly females (60%), with a median age of 50 years (range, 29–71 years). Disease-free survival (DSS) ranged from 8 to 132 months of follow-up, with 65% of the patients developing recurrence in the allotted follow-up time. Gross total resection was accomplished in 15% of the patients, and we report a 100% disease-specific survival in our cohort. Gene expression analysis of these tumors uncovered 56 genes that were significantly upregulated or downregulated in our cohort. Thirty-one genes were involved in cellular signal transduction pathways, 21 genes in immune system function, 14 genes involved in transcription regulation, 9 genes involved in cell development, 6 genes involved in cellular metabolism, and 3 genes were involved in axonal guidance pathways (overlapping occurring).

Conclusion: These findings provide a framework to evaluate tumor recurrence risk in patients with schwannoma based on RNA-sequencing results. Our results implicate immune system dysregulation as an associated factor in early schwannoma recurrence, suggesting the potential for immunotherapy as a treatment for schwannomas. As sequencing technology becomes increasingly available, these findings can guide future treatment decisions regarding the extent of therapy, including both surgical resection and radiotherapy.