OS6.4 Molecular classification of meningiomas across all histological subtypes and grades

Abstract

The current WHO classification recognizes 15 subtypes of meningioma distributed across three grades of malignancy. Allocation to subtype is based on histological findings. For other brain tumors, molecular profiling has already identified novel subsets beyond histological definitions. Here, we set out to identify novel clinically relevant subgroups of meningioma and reliable molecular markers by methylation and mutational profiling of 416 samples across all subtypes. Unsupervised clustering of methylation data from 450k array on 158 meningiomas (Discovery cohort) revealed six epigenetic subgroups. All cases were subsequently analyzed by targeted re-sequencing of a panel of genes. Selected cases of each group were subjected to exome-sequencing. The most prominent epigenetic difference was found between a cluster encompassing the majority of grade III cases (“ANAP” cluster) and the remaining grade II and grade I samples. This subgroup carried mutations in chromatin-modifiers (e.g. CREBBP and others). Among the remaining five clusters, four were associated with distinct patterns of histology: One harboured predominantly meningothelial cases and several transitional cases, all with AKT1 or SMO mutations (“MEN”cluster). The second encompassed fibrous, psammomatous and transitional cases with NF2 mutations (“FIBRO” cluster). The third harboured angiomatous, metaplastic and microcystic cases, the majority with gain of chromosome 5 (“ANGIO” cluster). The fourth contained all cases of secretory meningioma with combined KLF4/TRAF7 mutations (“SECR” cluster). One cluster harboured samples of varying histology with a predominance of atypical grade II cases (“ATYP” for atypical). These cases were enriched for mutations in genes of the PI3K pathway other than AKT1. These subgroups hold true on an extended set of 416 samples and allocation to the subgroup was stable during progression. Importantly, these subgroups were associated with distinct clinical behavior. Stratification based on these subgroups allowed for more accurate prognostication than grading according to the WHO classification. Collectively, these data identify stable genetic subgroups among meningiomas, providing the basis for a refinement of meningioma classification with molecular markers.