ARID1A and TERT promoter mutations in dedifferentiated meningioma

Abstract

While WHO grade I meningiomas are considered benign, patients with WHO grade III meningiomas have very high mortality. The principles underlying tumor progression in meningioma are largely unknown yet a detailed understanding of these mechanisms will be required for effective management of patients with these high-grade, lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity – comprised of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II and III designations. The lowest-grade regions had classic meningothelial features while the highest grade regions were markedly dedifferentiated. While progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies the current case offers us a snapshot into histologic progression and intratumor heterogeneity in a native, pre-treatment context. Using whole exome sequencing (WES) and high resolution array comparative genomic hybridization (aCGH) we observe marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we find increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TERT promoter and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.

Genomic landscape of high-grade meningiomas

“…We also sequenced selected genes in 76 additional high-grade meningiomas for a total of 134 high-grade meningiomas (Supplementary Table 1 & Supplementary Figure 1). We compared the data derived from these 134 samples to previously published data from 595 sporadic meningiomas profiled with whole genome or whole exome sequencing (108 low-grade and 22 high-grade tumors tumors), and targeted capture sequencing (348 low-grade and 117 high-grade tumors) [6, 7, 9–12]. We used these data to characterize somatic mutations (including insertions and deletions), somatic copy-number alterations (SCNAs), and rearrangements genome-wide.…”

“…To evaluate this possibility, we sequenced these genes, which are the four most common non- NF2 driver alterations, in our extension cohort of 76 samples. We then integrated the data with previously published sequencing data from 595 additional meningiomas [6, 7, 9, 10, 12]. For each gene, we compared rates of mutation among both high- and low-grade meningiomas (Figure 1D) [6, 7].…”

Decreased FOXJ1 expression and its ciliogenesis programme in aggressive ependymoma and choroid plexus tumours

“…Antigen retrieval was with a pressure cooker. Staining was attempted with anti-HFH4 antibody [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] (ab40869; Abcam, Cambridge, MA, USA) but despite recognizing FOXJ1 in ciliated Fallopian tube cells, staining was not obtained in ependymoma tumour cells. Negative control staining was performed using normal/non-immune rabbit serum, immunoglobulin fraction (X0936; DakoCytomation Corp, Carpinteria, CA, USA).…”

DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

“…epigenetic subgroups in medulloblastoma [8][9][10] and ependymoma 11 , or isocitrate dehydrogenase (IDH) status in diffuse glioma [12][13][14] . Recent studies identified telomerase reverse transcriptase (TERT) promoter mutations in a small subset of meningiomas to be associated with higher risk of recurrence and shorter time to progression 15,16 , and four large exome-sequencing efforts focusing on WHO grade I meningiomas have identified recurrently mutated genes beyond the long-known association with NF2 [17][18][19][20] . Yet, these findings only cover only a fraction of meningiomas and have not all been adequatelythoroughly tested for their prognostic relevance.…”