EPCO-42. RECURRENT LMNA-FOSB FUSIONS ALTER CHROMATIN TOPOLOGY AND GENE REGULATION IN MENINGIOMAS

Abstract Meningiomas are among the most prevalent tumors of the central nervous system and are typically driven by a limited set of mutually exclusive genetic alterations. We report molecular characterization of seven meningiomas with fusions between LMNA and FOSB, in the absence of other canonical meningioma-associated mutations. LMNA, encoding nuclear envelope protein Lamin A/C, plays a central role in chromatin architecture and is widely expressed across differentiated tissues. FOSB, an AP-1 transcription factor, regulates genes involved in cellular growth and differentiation. Using integrated genomic analyses—including targeted DNA sequencing, whole-genome sequencing, and RNA-seq—we validated near identical fusions involving exons 1–2 of LMNA (chr1) and exons 2–4 of FOSB (chr19). This rearrangement retains key functional domains from both genes, notably the Ser22 phosphorylation site in Lamin A/C that associates with active enhancers, and the DNA-binding region of FOSB. Transcript levels of LMNA and FOSB remained largely unaltered in fusion-positive tumors, suggesting oncogenic activity may stem from a neomorphic fusion protein rather than dysregulated gene expression. Expression of LMNA-FOSB constructs in CH157 and IOMM-LEE meningioma cell lines led to significant alterations in chromatin structure and transcriptional profiles. Gene set enrichment analysis of upregulated genes (FC > 1, P < 0.05) shared between transfected CH157 and IOMM-LEE lines revealed enrichment of pathways related to laminin, fibronectin, and collagen binding—components commonly elevated in the meningioma extracellular matrix—as well as growth factor binding (P < 0.05). These findings were corroborated by Hi-C and ChIP-seq profiling of patient-derived frozen tumors, which demonstrated changes in chromatin conformation and transcriptional regulation. Our data establish LMNA-FOSB fusions as a novel and recurrent genetic alteration in meningiomas, illuminating a potential oncogenic mechanism involving chromatin remodeling and transcriptional reprogramming, and expanding the known functional scope of FOSB fusions in cancer.