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.
Highlights
Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord
We found that DNA methylation levels in malignant meningioma are significantly lower than those in atypical or benign tumors (Figure 1, p,0.05 by twotailed t-test)
Further analysis showed that probes targeting different gene regions such as TSS200, TSS1500, 1st Exon, Gene Body, 39UTR, 59UTR all have decreased mean b values in malignant meningiomas, suggesting that DNA hypomethylation is not limited to specific gene regions but rather occurs throughout the genome
Summary
Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. They are the most frequently diagnosed primary brain tumor, accounting for 33.8% of all primary brain tumors in the United States, with an annual incidence of 40 to 60 cases per million persons [1,2]. Meningiomas are classified as benign (grade I), atypical (grade II), or anaplastic/malignant (grade III) according to the World Health Organization (WHO) histological grading criteria. They represent 80%, 15% and 5% of all meningiomas respectively [3]. Because the prognosis for malignant meningiomas remains much worse than benign or atypical meningiomas, any characterization of genetic or epigenetic processes involved in malignant transformation may provide important insights into novel diagnostic and therapeutic strategies aimed at understanding this aggressive tumor subtype
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