An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Grace Collord,C Oliver Hanemann,Ultan Mcdermott,Patrick Tarpey,Adam M H Young,Matthew D Young,Matthias Kirsch,Gabriele Schackert,Graham R Bignell ,Tibor Nagy,Sebastián Morán ,Rasheed Zakaria,Sam Behjati,V Peter Collins,Imran Noorani,Christopher E Mcmurran ,Michael W Mcdermott,Khaja Syed,José M C Tubío ,Zvi Ram,Michael D Jenkinson,Ramez Kirollos ,Manuel Castro,Kieren Allinson,Mathijs A Sanders ,Alvis Brāzma ,Colin Watts,Elke Leipnitz,Manel Esteller,Iñigo Martincorena ,Danita M Pearson ,George S Vassiliou,Jemma Dunn,Stephen J Price,Abel Devadass,Francesco Maura,Natalja Kurbatova,Jorge Berna,Thomas Santarius

doi:10.1038/s41598-018-31659-0

Abstract

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.

Highlights

We performed whole genome sequencing (WGS) on a discovery set of 19 anaplastic meningiomas resected at first presentation (‘primary’)
Given the propensity of anaplastic meningioma to recur, we studied by whole genome sequencing 13 recurrences from 7 patients
In the combined cohort of 50 primary tumors, we found at least one driver mutation in NF2 in 70%, similar to the prevalence reported in atypical meningiomas and more than twice that found in grade I tumors[7,9]

Summary

Introduction

A recent study of 775 grade I and grade II meningiomas identified five molecular subgroups defined by driver mutation profile[7]. Despite the high mortality rate of anaplastic meningiomas, efforts to identify adjuvant treatment strategies have been hampered by a limited understanding of the distinctive molecular features of this aggressive subtype. A recent analysis of meningioma methylation profiles identified distinct subgroups within Grade III tumors predictive of survival outcomes, though the biology underpinning these differences and any therapeutic implications remain unknown[10]. We present an analysis of the genomic, transcriptional and DNA methylation patterns defining anaplastic meningioma. Our results reveal molecular hallmarks of aggressive disease and suggest novel approaches to risk stratification and targeted therapy

Methods

Results

Conclusion