Optic nerve sheath meningioma exhibits neural niche‐associated transcriptomic features and rare <scp>copy number variation</scp> ‐linked evolution

Optic nerve sheath meningioma (ONSM) is a rare tumor that arises from the meninges enveloping the optic nerve. Although the genetic landscape of meningiomas has been extensively studied, the molecular alterations underlying ONSM remain poorly understood. We retrospectively analyzed consecutive patients surgically treated for ONSM between 2000 and 2025 at our institution, with available histological specimens. Intracranial meningiomas secondarily extending into the optic canal were excluded. Fresh-frozen tumor samples were subjected to whole-exome sequencing, and transcriptomic analyses were conducted and compared with those of intracranial meningiomas from four public datasets. Six cases were included, five of whom were female, with a median age of 63.5 years. While most cases remained stable after surgery, one patient experienced multiple recurrences and ultimately succumbed. Primary tumors were characterized by the absence of NF2 alterations, occasional POLR2A mutations, and few copy number variations (CNVs). Transcriptomic profiling in primary tumors revealed a neurotrophic microenvironment reflective of the close association with the optic nerve. The recurrent case exhibited high-risk CNVs at diagnosis and developed into an aggressive disease as additional CNV burdens accumulated, including the homozygous deletion of CDKN2A/B. Its expression profile was in line with that of hypermitotic, proliferative intracranial meningiomas. ONSM represents a predominantly NF2-intact meningioma subtype defined by neural niche-associated transcriptional signatures. Although typically indolent, ONSM can, in rare instances, evolve into an aggressive disease through further accumulation of CNVs.