Multiplatform Molecular Profiling of Vestibular Schwannoma Reveals 2 Subgroups of Tumors With Distinct Radiographic Features and a Methylation-Based Predictor of Local Recurrence

Abstract

Abstract INTRODUCTION Vestibular schwannomas (VS) can cause significant morbidity from cranial neuropathies and mass effect. Broad molecular differences have been described for intracranial versus spinal axis schwannomas, but little is known about the molecular heterogeneity of VS or predictors of recurrence. METHODS A total of 66 sporadic VS from 59 consecutive patients with available tissue who underwent initial resection (44), resection for recurrence after prior surgery (5), resection for recurrence after prior stereotactic radiosurgery (SRS) (11), or resection after both prior surgery and prior SRS (6) at a single institution from 2003 to 2017 were profiled using 850 K DNA methylation arrays (median follow-up: 4.2 yr, median volumetric resection: 91%). A total of 24 VS were further characterized using RNA sequencing. Molecular subtyping was performed using differential-DNA methylation analysis and validated using transcriptomic data. Preoperative magnetic resonance imaging (MRI) studies were centrally reviewed by a board-certified neuro-radiologist. RESULTS NA methylation profiling revealed 2 novel subgroups of VS, delineated by enrichment of neural crest genes (31 tumors) or immune genes (35 tumors). Neural crest-enriched VS were more likely to show reduced diffusion on MRI (P < .01), while immune-enriched VS were more likely to show cystic changes (P < .05), mass effect (P < .01), and edema (P < .05). Immune-enriched VS were significantly more likely to be adherent to the brainstem and left as residual at the time of resection. A total of 15 immune-enriched VS (43%) had prior SRS, while only 2 neural crest-enriched VS (6%) had prior SRS (P < .001). Hypomethylation of G protein-coupled estrogen receptor 1 (GPER) promoter was prognostic for local failure in multivariate regression irrespective of primary treatment modality (P < .0001). CONCLUSION VS are comprised of 2 molecular subgroups characterized by differential enrichment of neural crest or immune genes. VS treated with prior SRS are associated with immune-enrichment. GPER promoter hypomethylation is prognostic for VS recurrence. These data illuminate the biology of VS and shed light on potential molecular therapies.