Comprehensive Molecular Profiling of Pediatric Meningioma

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Meningiomas are a common central nervous system (CNS) tumor that arise from arachnoidal cells of the meninges that cover and protect the brain and spinal cord. The World Health Organization (WHO) classification strategy defines meningiomas into three pathologically distinct groups based on morphological features, such as cellularity, mitotic activity, cell morphology, necrosis, and brain invasion: WHO Grade I benign meningioma (70-80%), WHO Grade II atypical meningioma (5-15%), and WHO Grade III anaplastic meningioma (1-2%). WHO Grade I meningiomas are the most common and typically slow-growing. Grade II atypical meningiomas may exhibit more aggressive behavior, including increased proliferation, brain invasion, and/or higher recurrence risk, while Grade III anaplastic meningiomas are malignant tumors. In general, meningiomas are more frequent in females and in individuals of older age. Meningiomas occurring in the pediatric and young adult population account for <1% of total cases for this collectively common tumor.

Compared to other adulthood tumors, meningiomas have a relatively low rate of somatic mutation and copy number alterations. Constitutional neurofibromatosis type 2, a rare genetic disorder, predisposes patients to meningiomas. We identified a YAP1-FAM118B fusion in a pediatric meningioma patient enrolled on our translational cancer protocol at Nationwide Children’s Hospital (NCH). This exceedingly rare fusion, harboring the same breakpoints, was reported once in a supratentorial ependymoma and has been associated with the YAP fusion ependymoma subgroup. Further studies are need to assess the frequency of this fusion in pediatric meningioma and to better understand the mechanisms of YAP activation in NF2-independent disease development and potential therapeutic options are needed.

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What are the goals of this project?

The goals of this project are to identify molecular pathways associated with YAP1 fusion meningioma relative to pediatric meningioma driven by other genetic drivers, including NF2, AKT1, TRAF7, and SMO. We will correlate clinical pathology with genetic drivers to identify if there are distinct histopathological features associated with YAP1 fusion and to better understand the mechanism of NF2-independent meningioma tumorigenesis, the transcriptomic profile of YAP1 fusion and known NF2-driven meningiomas will be examined. The goal of this aim is to identify therapeutic molecular targets associated with the rare YAP1 fusion meningioma subgroup.

What is the impact of this project?

Pediatric meningioma is exceedingly rare; thus, studying the molecular mechanism of tumorigenesis is challenging. Furthermore, a majority of these tumors are associated with a well-described genetic disorder, neurofibromatosis type 2, for which the biological mechanism of disease has been described. Tumors that do not harbor an NF2 variation are rare but lend themselves to the potential for novel molecular mechanisms and therapeutic considerations. Through describing a novel subgroup of pediatric meningioma, we hope to provide targeted therapeutic options for patients with recurrence or for whom a gross total resection may not be feasible.

Why the CBTN request is important to this project?

Pediatric meningiomas are a rare entity among a collectively common tumor, accounting for <1% of all meningioma cases. The CBTN has a cohort of 11 pediatric meningioma tumors, a significant number of cases when a metaanalysis collected 534 cases in a 21-year period. Of these cases, one patient harbors the same fusion event (YAP1- FAM118B) as a patient recently identified on our translational cancer protocol at Nationwide Children’s Hospital. Although, only two cases have now been identified, incorporating the patient from the CBTN harboring the YAP1 fusion, and the patients with other known genetic drivers will allow us to better understand the NF2-independent mechanism of meningioma tumorigenesis.

Specimen Data

The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.

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