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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA methylation in the malignant transformation of meningiomas
Fan Gao1, Lingling Shi, Jonathan Russin
1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Abstract:
Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Most meningiomas are pathologically benign or atypical, but 3-5% display malignant features. Despite previous studies on benign and atypical meningiomas, the key molecular pathways involved in malignant transformation remain to be determined, as does the extent of epigenetic alteration in malignant meningiomas. In this study, we explored the landscape of DNA methylation in ten benign, five atypical and four malignant meningiomas. Compared to the benign tumors, the atypical and malignant meningiomas demonstrate increased global DNA hypomethylation. Clustering analysis readily separates malignant from atypical and benign tumors, implicating that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. Genes with hypermethylated CpG islands in malignant meningiomas (such as HOXA6 and HOXA9) tend to coincide with the binding sites of polycomb repressive complexes (PRC) in early developmental stages. Most genes with hypermethylated CpG islands at promoters are suppressed in malignant and benign meningiomas, suggesting the switching of gene silencing machinery from PRC binding to DNA methylation in malignant meningiomas. One exception is the MAL2 gene that is highly expressed in benign group and silenced in malignant group, representing de novo gene silencing induced by DNA methylation. In summary, our results suggest that malignant meningiomas have distinct DNA methylation patterns compared to their benign and atypical counterparts, and that the differentially methylated genes may serve as diagnostic biomarkers or candidate causal genes for malignant transformation.
Insights
Malignant meningiomas show distinct DNA methylation patterns compared to benign tumors. These epigenetic changes, including global hypomethylation and specific gene silencing, may serve as biomarkers for diagnosing meningioma malignancy.
Area of Science:
- Neuro-oncology
- Epigenetics
- Cancer Genomics
Background:
- Meningiomas are tumors arising from the brain and spinal cord's meningeal coverings.
- While most meningiomas are benign or atypical, 3-5% exhibit malignant characteristics.
- The molecular mechanisms driving malignant transformation and epigenetic alterations in these tumors are not fully understood.
Purpose of the Study:
- To investigate the DNA methylation landscape in benign, atypical, and malignant meningiomas.
- To identify key molecular pathways and epigenetic alterations associated with malignant meningioma development.
- To explore the potential of DNA methylation patterns as diagnostic biomarkers for meningioma malignancy.
Main Methods:
- Analysis of DNA methylation patterns across ten benign, five atypical, and four malignant meningioma samples.
- Global DNA methylation assessment and clustering analysis of tumor subtypes.
- Identification and characterization of differentially methylated genes, including promoter CpG island methylation and gene expression analysis.
Main Results:
- Malignant and atypical meningiomas exhibit increased global DNA hypomethylation compared to benign tumors.
- Clustering analysis based on DNA methylation patterns effectively distinguishes malignant from benign and atypical meningiomas.
- Hypermethylated genes in malignant meningiomas, such as HOXA6 and HOXA9, correlate with Polycomb Repressive Complex (PRC) binding sites.
- Suppression of genes with hypermethylated CpG islands suggests a shift in gene silencing mechanisms from PRC binding to DNA methylation in malignant transformation.
- The MAL2 gene shows de novo silencing via DNA methylation in malignant meningiomas, contrasting with its high expression in benign tumors.
Conclusions:
- Malignant meningiomas possess unique DNA methylation profiles differentiating them from benign and atypical subtypes.
- Differentially methylated genes in malignant meningiomas hold promise as diagnostic biomarkers.
- These epigenetic alterations may play a causal role in the malignant transformation of meningiomas.
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