ARID1A and TERT promoter mutations in dedifferentiated meningioma

Abstract

Unlike patients with World Health Organization (WHO) grade I meningiomas, which are considered benign, patients with WHO grade III meningiomas have very high mortality rates. 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-composed 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. Whereas progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies, the current case offers us a snapshot of histologic progression and intratumoral heterogeneity in a native pretreatment context. Using whole exome sequencing and high resolution array-based comparative genomic hybridization, we observed marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we found 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.

Keywords: Meningioma; SWI/SNF complex; anaplastic; chromatin remodeling; intratumoral heterogeneity.

Figure 1

Intratumoral heterogeneity within a high-grade meningioma. (A) T1-weighted gadolinium-enhanced axial MRI demonstrating a heterogeneously appearing contrast-avid tumor within the atrium of the right lateral ventricle, with (B) significant peritumoral edema and associated hydrocephalus on the T2-weighted axial MRI. (C) Post-operative T1-weighted axial MRI demonstrating complete resection. (D) Section of tumor, with 3 distinct appearing histologic regions (designated areas 1, 2, 3). Immunohistochemistry for epithelial membrane antigen (EMA) and MIB-1 (Ki-67). Scale bar, 10 μm.

Figure 2

Genetic heterogeneity within a high-grade meningioma. (A) High-resolution aCGH was performed on DNA extracted from core punches taken from area 1 (WHO grade I), area 2 (WHO grade II), and area 3 (WHO grade III), using 1×1M Agilent SurePrint G3 Human CGH Microarray chip [3,30]. Red indicates gain and blue indicates loss. (B) Copy number analysis from exome-sequencing data of the three areas shown as allelic copy ratios. Red indicates gain and blue indicates loss. (C) In situ hybridization of TERT mRNA transcripts using a TERT-specific RNAscope probe in FFPE sections of the meningioma samples [10,14]. (D) Immunohistochemistry for ARID1A. (E) Schematic representation of clonal evolution leading to dedifferentiation and intratumoral heterogeneity. Scale bar, 10 μm.