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Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

ABSTRACT: Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.

SUBMITTER: Magill ST

PROVIDER: S-EPMC7511976 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

Magill Stephen T ST Vasudevan Harish N HN Seo Kyounghee K Villanueva-Meyer Javier E JE Choudhury Abrar A John Liu S S Pekmezci Melike M Findakly Sarah S Hilz Stephanie S Lastella Sydney S Demaree Benjamin B Braunstein Steve E SE Bush Nancy Ann Oberheim NAO Aghi Manish K MK Theodosopoulos Philip V PV Sneed Penny K PK Abate Adam R AR Berger Mitchel S MS McDermott Michael W MW Lim Daniel A DA Ullian Erik M EM Costello Joseph F JF Raleigh David R DR

Nature communications 20200923 1

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underli ...[more]

PMID: 32968068

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Project description:ObjectiveTo determine whether tumor shear stiffness, as measured by magnetic resonance elastography, corresponds with intratumoral consistency and histotype.Materials and methodsA total of 88 patients with 89 meningiomas (grade 1, 74 typical [13 fibroblastic, 61 non-fibroblastic]; grade 2, 12 atypical; grade 3, 3 anaplastic) were prospectively studied, each undergoing preoperative MRE in conjunction with T1-, T2- and diffusion-weighted imaging. Contrast-enhanced T1-weighted sequences were also obtained. Tumor consistency was evaluated as heterogeneous or homogenous, and graded on a 5-point scale intraoperatively. MRE-determined shear stiffness was associated with tumor consistency by surgeon's evaluation and whole-slide histologic analyses.ResultsMean tumor stiffness overall was 3.81+/-1.74 kPa (range, 1.57-12.60 kPa), correlating well with intraoperative scoring (r = 0.748; p = 0.001). MRE performed well as a gauge of tumor consistency (AUC = 0.879, 95 % CI: 0.792-0.938) and heterogeneity (AUC = 0.773, 95 % CI: 0.618-0.813), significantly surpassing conventional MR techniques (DeLong test, all p < 0.001 after Bonferroni adjustment). Shear stiffness was independently correlated with both fibrous content (partial correlation coefficient = 0.752; p < 0.001) and tumor cellularity (partial correlation coefficient = 0.547; p < 0.001). MRE outperformed other imaging techniques in distinguishing fibroblastic meningiomas from other histotypes (AUC = 0.835 vs 0.513 ∼ 0.634; all p < 0.05), but showed limited ability to differentiate atypical or anaplastic meningiomas from typical meningiomas (AUC = 0.723 vs 0.616 ∼ 0.775; all p > 0.05). Small (<2.5 cm, n = 6) and intraventricular (n = 2) tumors displayed inconsistencies between MRE and surgeon's evaluation.ConclusionsThe results of this prospective study provide substantial evidence that preoperative evaluation of meningiomas with MRE can reliably characterize tumor stiffness and spatial heterogeneity to aid neurosurgical planning.

Dataset Information

Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

Publications

Multiplatform genomic profiling and magnetic resonance imaging identify mechanisms underlying intratumor heterogeneity in meningioma.

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