PATH-02. NOVEL SOX10 INDEL MUTATIONS DRIVE SCHWANNOMAS THROUGH IMPAIRED TRANSACTIVATION OF MYELINATION GENE PROGRAMS

Abstract

Abstract Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity due to their stereotypic intracranial and paraspinal locations. However, the molecular drivers responsible for a substantial subset remain unknown. Through genomic profiling of 96 schwannomas, we identified novel in-frame insertion/deletion mutations in the SOX10 gene in 29% of sporadic tumors which uniformly lacked alterations in known nerve sheath tumor genes including NF1, NF2, LZTR1, and SMARCB1. These indel mutations clustered at the C-terminal end of the HMG-box domain, the DNA binding motif of the SOX10 transcription factor critical for Schwann cell differentiation. Schwannomas arising from non-vestibular cranial nerves (e.g. facial, trigeminal, vagus) were highly enriched for SOX10 mutations, whereas the vast majority of vestibular schwannomas had NF2 inactivation. DNA methylation profiling revealed that SOX10 mutant schwannomas clustered together with schwannomas harboring NF2 mutation or SH3PXD2A-HTRA1 fusion, indicating that SOX10 indel mutations define a novel schwannoma molecular subtype and not a distinct nerve sheath tumor entity. To investigate the mechanism by which SOX10 indel mutations promote schwannoma development, we stably transduced human fetal glial cells with either wildtype SOX10 or two different tumor-derived insertion mutants. RNA sequencing revealed that both SOX10 indel mutants, in contrast to wildtype SOX10, failed to activate expression of myelination and glial differentiation gene programs, including PMP2 which encodes the major peripheral myelin protein in mature Schwann cells. Electrophoretic mobility shift assay revealed that the indel mutants retained their DNA binding capacity to the SOX10 binding site in the PMP2 promoter, while a luciferase reporter assay revealed transactivation at the PMP2 promoter by wildtype SOX10 but not by the mutants. In summary, we identified a new recurrent genetic event in 29% of sporadic schwannomas that we speculate drives schwannoma development through impaired transactivation of myelination gene expression programs causing blocked differentiation of immature Schwann cells.