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Multisite methylation profiling of primary human meningioma

ABSTRACT: Multiple stereotatically separate sites from human meningioma were processed for methlyation profiling 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, we performed 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 demonstrated that high apparent diffusion coefficient (ADC) distinguished meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we developed a human cerebral organoid model of meningioma and validated 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151067 | GEO | 2020/06/17

REPOSITORIES: GEO

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Project description:Purpose: In this study, we try to investigate the possible signaling pathways involved in the tumorigenesis of fibroblastic and anaplastic meningiomas. We also attempt to investigate EGFL6 gene expression in brain arachnoidal tissues and various tumors and to measure EGFL6 levels in serum samples from healthy people and patients with various tumors by using ELISA. Experimental Design: Differential gene expression profiles between meningiomas and brain arachnoidal tissues were established by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis was performed to identify potential gene pathways that may be involved in the pathogenesis of meningiomas. Quantitative real-time PCR (qRT-PCR) was performed to validate the differentially expressed genes in the KEGG pathways. EGFL6 mRNA levels were also determined in brain arachnoidal tissues, meningiomas, and other tumors by qRT-PCR. EGFL6 levels were measured in serum samples from healthy people and patients with various tumors by using ELISA. Results: Fibroblastic meningioma exhibited upregulated PI3K/Akt and TGFÎ² signaling pathways, and accelerated G1/S progression cell cycle. KEGG analysis also demonstrated that focal adhesion and ECM-receptor interaction pathways were activated in anaplastic meningioma. Benign meningiomas had significantly higher levels of EGFL6 mRNA than brain arachnoidal tissues and atypical and anaplastic meningiomas (P<0.001). EGFL6 gene was also highly expressed in ovarian cancer, but expressed lowly in all other investigated tumors. EGFL6 was hardly detectable in serum samples of healthy people. The mean serum EGFL6 concentration was 675, 118, and 126 pg/ml in patients with benign, atypical, and anaplastic meningiomas respectively. Patients with ovarian cancers also had high serum EGFL6 levels (mean concentration: 617 pg/ml). Patients with all other investigated tumors, however, had low levels of serum EGFL6 with mean concentration less than 240 pg/ml. Conclusion: We proposed that deregulation of cell cycle and PI3K/Akt pathways might play important roles in the tumorigenesis of fibroblastic meningioma. It was also suggested that the activated integrin-mediated signaling pathways were involved in the pathogenesis of anaplastic meningioma. We presented evidence that EGFL6 might serve as a novel serum biomarker for benign meningioma and ovarian cancer. It was also suggested that EGFL6 could help discriminate benignancy or malignancy of meningiomas before surgery or at early time points. Differential gene expression profiles between meningiomas and brain arachnoidal tissues were established by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis was performed to identify potential gene pathways that may be involved in the pathogenesis of meningiomas. Quantitative real-time PCR (qRT-PCR) was performed to validate the differentially expressed genes in the KEGG pathways. EGFL6 mRNA levels were also determined in brain arachnoidal tissues, meningiomas, and other tumors by qRT-PCR. EGFL6 levels were measured in serum samples from healthy people and patients with various tumors by using ELISA.

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Multisite methylation profiling of primary human meningioma

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