Targeted DNA sequencing identifies specific mutations associated with clinical presentation and functional outcomes in sporadic schwannomas

Objective: Benign peripheral nerve sheath tumors (BPNSTs) are comprised of schwannomas, neurofibromas, and hybrid nerve sheath tumors. While these tumors can be associated with syndromes (NF1, NF2/SWN), the majority occur sporadically. The literature is limited in associating molecular and sequencing data of this cohort with clinical presentation and outcome. This study aims to define relationships between molecular pathology and clinical outcomes through targeted DNA sequencing. Methods: A single institution study was conducted with patients harboring a non-syndromic BPNST who underwent surgical resection by the senior author between October 2014 and May 2025 at a major tertiary center. Pre-operative clinical presentation and post-operative functional outcomes were assessed with the corresponding molecular analysis. Results: The entire cohort consisted of 219 BPNSTs; of which 75 schwannomas and 9 hybrid tumors underwent in-house-targeted next-generation DNA sequencing. In patients undergoing DNA sequencing, 83/84 (99%) of BPNSTs harbored at least one pathogenic variant. Among the 75 sporadic schwannomas that underwent DNA sequencing, a total of 120 pathogenic or likely pathogenic variants across 16 unique genes were detected, with NF2 mutations being the most common (n=46, 38% of mutations). While NF2 mutations included all variant types, recurrent SOX10, 22q, and SH3 alterations were limited to exhibited insertion/ deletions, whole gene deletions, and fusions, respectively. The rate of a post-operative sensory deficit at last follow-up was higher in patients with NF2 mutant tumors compared to NF2 wildtype tumors (p=.008, OR =12). Discussion: Targeted DNA sequencing of BPNSTs revealed specific mutations correlated with clinical presentation and functional outcome.