Abstract 6616: LMNA-FOSB fusions are a recurrent event in meningiomas

Meningiomas are common tumors of the central nervous system associated with a small number of mutually exclusive genetic events. We identify a cohort of seven meningiomas that harbor fusions between the genes LMNA and FOSB, with no other known meningioma mutations. Previous reports of LMNA-FOSB fusions in epithelioid hemangiomas suggest a broader oncogenic potential for this event across tumor types. Lamin A/C is a structural protein involved in chromatin organization expressed ubiquitously in nearly all differentiated cells, while FOSB is an AP-1 family transcription factor implicated in cell proliferation and differentiation. Targeted, whole-genome, and RNA-sequencing approaches revealed a near identical LMNA-FOSB fusion comprising exons 1-2 of LMNA (chr1) and exons 2-4 of FOSB (chr19). The fusion event therefore includes key phosphorylation sites in Lamin A/C such as Ser22 that interact with active enhancers, while preserving the DNA binding domain of FOSB. Expression of these genes was not significantly altered among fusion samples, suggesting neomorphic protein function as an underlying oncogenic mechanism. Transfection of the LMNA-FOSB constructs into CH157 and IOMM-LEE meningioma cell lines resulted in changes to chromatin architecture and gene expression, which were validated using Hi-C and ChIP-seq profiling of frozen tumor tissues harboring this event. Our findings suggest that LMNA-FOSB fusions represent a novel and recurrent meningioma genetic event, providing new insights into the molecular pathogenesis of these tumors and role of FOSB across cancer. Citation Format: Mateo Gomez Hjerthen, Josiah Wong, Juan Wang, Harrshavasan Congivaram, Priscilla K. Brastianos, Akash J. Patel, Craig M. Horbinski, James P. Chandler, E. Zeynep Erson Omay, Jennifer Moliterno, Murat Günel, Stephen T. Magill, David R. Raleigh, Feng Yue, Mark W. Youngblood. LMNA-FOSB fusions are a recurrent event in meningiomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6616.