Original ArticlesYAP1-FAM118B Fusion Defines a Rare Subset of Childhood and Young Adulthood MeningiomasSchieffer, Kathleen M. PhD*; Agarwal, Vibhuti MD†; LaHaye, Stephanie PhD*; Miller, Katherine E. PhD*; Koboldt, Daniel C. MS*,‡; Lichtenberg, Tara MS*; Leraas, Kristen MS*; Brennan, Patrick MS*; Kelly, Benjamin J. MS*; Crist, Erin MMSc, LGC*; Rusin, Jerome MD§; Finlay, Jonathan L. MBChB, FRCP, FRCPCH†,‡,∥; Osorio, Diana S. MD†,‡,∥; Sribnick, Eric A. MD, PhD¶,#; Leonard, Jeffrey R. MD¶,#; Feldman, Alexander MD**; Orr, Brent A. MD, PhD††; Serrano, Jonathan BS‡‡; Vasudevaraja, Varshini MS‡‡; Snuderl, Matija MD‡‡; White, Peter PhD*,‡; Magrini, Vincent PhD*,‡; Wilson, Richard K. PhD*,‡; Mardis, Elaine R. PhD*,‡; Boué, Daniel R. MD, PhD**,§§; Cottrell, Catherine E. PhD*,‡,§§Author Information *The Steve and Cindy Rasmussen Institute for Genomic Medicine †Division of Hematology, Oncology, and Bone Marrow Transplant ¶Division of Neurosurgery Departments of §Radiology **Pathology and Laboratory Medicine, Nationwide Children’s Hospital Departments of ‡Pediatrics #Neurosurgery §§Pathology ∥Division of Hematology and Oncology, The Ohio State University College of Medicine, Columbus, OH ††St. Jude Children’s Research Hospital, Memphis, TN ‡‡Department of Pathology, New York University Langone Health, New York City, NY This research was conducted using data made available by The Children’s Brain Tumor Tissue Consortium (CBTTC). Conflicts of Interest and Source of Funding: The Nationwide Foundation Pediatric Innovation Fund provided funding for sequencing, data production, and analysis. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Kathleen M. Schieffer, PhD, The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, 575 Children’s Crossroad, WB2250, Columbus, OH 43215 (e-mail: [email protected]). The American Journal of Surgical Pathology: March 2021 - Volume 45 - Issue 3 - p 329-340 doi: 10.1097/PAS.0000000000001597 Buy SDC Metrics Abstract Meningiomas are a central nervous system tumor primarily afflicting adults, with <1% of cases diagnosed during childhood or adolescence. Somatic variation in NF2 may be found in ∼50% of meningiomas, with other genetic drivers (eg, SMO, AKT1, TRAF7) contributing to NF2 wild-type tumors. NF2 is an upstream negative regulator of YAP signaling and loss of the NF2 protein product, Merlin, results in YAP overexpression and target gene transcription. This mechanism of dysregulation is described in NF2-driven meningiomas, but further work is necessary to understand the NF2-independent mechanism of tumorigenesis. Amid our institutional patient-centric comprehensive molecular profiling study, we identified an individual with meningioma harboring a YAP1-FAM118B fusion, previously reported only in supratentorial ependymoma. The tumor histopathology was remarkable, characterized by prominent islands of calcifying fibrous nodules within an overall collagen-rich matrix. To gain insight into this finding, we subsequently evaluated the genetic landscape of 11 additional pediatric and adolescent/young adulthood meningioma patients within the Children’s Brain Tumor Tissue Consortium. A second individual harboring a YAP1-FAM118B gene fusion was identified within this database. Transcriptomic profiling suggested that YAP1-fusion meningiomas are biologically distinct from NF2-driven meningiomas. Similar to other meningiomas, however, YAP1-fusion meningiomas demonstrated overexpression of EGFR and MET. DNA methylation profiling further distinguished YAP1-fusion meningiomas from those observed in ependymomas. In summary, we expand the genetic spectrum of somatic alteration associated with NF2 wild-type meningioma to include the YAP1-FAM118B fusion and provide support for aberrant signaling pathways potentially targetable by therapeutic intervention. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.