학술논문

Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs
Document Type
article
Source
Neuro-Oncology. 25(12)
Subject
Biomedical and Clinical Sciences
Clinical Sciences
Pediatric
Cancer
Human Genome
Neurosciences
Biotechnology
Genetics
Rare Diseases
Aetiology
2.1 Biological and endogenous factors
Humans
INDEL Mutation
Transcriptional Activation
Neurilemmoma
Neuroma
Acoustic
Mutation
Nerve Sheath Neoplasms
SOXE Transcription Factors
myelination
PMP2
Schwann cell
schwannoma
SOX10
Oncology and Carcinogenesis
Oncology & Carcinogenesis
Oncology and carcinogenesis
Language
Abstract
BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.