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.