Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

Abstract

SUMMARYMeningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

Clinical significance of NF2 alteration in grade I meningiomas revisited; prognostic impact integrated with extent of resection, tumour location, and Ki-67 index

“…This finding is counterintuitive, considering that NF2 alteration are known to initiate events for aggressive-type meningiomas [ 36 ]. Actually, the latest trends of the molecular subgroups for meningioma focus on whether NF2 meningioma or not according to the data of single-cell RNA sequencing in meningiomas [ 25 , 37 , 38 ].…”

“…), high FOXM1 expression, low immune cell infiltration, and loss of H3K27me3 were reported as characteristics of aggressive behaviour of meningiomas [ 28 , 43 ]. Recent reports have speculated structure variants such as multiple CNVs, especially 1p loss, as an epigenetic “second-hit” following NF2 alteration for aggressive-type meningiomas [ 22 , 24 , 38 , 45 ]. Although we posit that supratentorial NF2 meningiomas might have such an aggressive feature as copy number alteration in addition to Ki-67 and FOXM1, it was beyond the scope of this study.…”

Multiple approaches converge on three biological subtypes of meningioma and extract new insights from published studies

“…Unfortunately, the field of meningioma has been slow to benefit from parallel efforts. NGS studies have associated certain mutations with specific histologic grades (8)(9)(10)(11)(12), and a number of epigenetic studies have linked methylation patterns to clinical outcomes (13)(14)(15)(16). In the largest such study to date, Sahm et al (14) performed unsupervised clustering of nearly 500 tumors across World Health Organization (WHO) grades and found two major epigenetic groups composed of six subclasses with distinct clinical and genomic features.…”