DNA Methylation in the Malignant Transformation of Meningiomas

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.

Is DNA methylation the new guardian of the genome?

“…Compared to benign tumors, atypical and malignant meningiomas were observed to have increased global DNA hypomethylation [12]. …”

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

“…With time, molecular advances allowed interrogation at a larger number of CpG loci [35] culminating with the methylation assays from Illumina (27k and 450k) interrogating approximately 27.000 and 450.000 CpG loci [74,21]. To the best of our knowledge only three studies addressed global methylation in meningiomas [35,74,21].…”

“…However, little is known about global methylation profiles of meningioma [21,35,74], and their clinical implications are not yet well understood. Moreover, a deeper understanding of methylation in meningioma may increase our understanding regarding meningioma tumorigenesis.…”

Genomic and transcriptome analysis revealing an oncogenic functional module in meningiomas

“…In a previous study, we also demonstrated that genome-wide methylation patterns cannot differentiate benign and atypical meningiomas but can easily differentiate malignant from benign/atypical samples. 11 Considering the small sample size for the atypical group and the low power to detect differential expression, we combined the benign and atypical samples and subsequently identified 288 differentially expressed genes between the malignant and benign/atypical sample groups. Hierarchical clustering analysis confirmed that the differentially expressed genes were clearly divided into these malignant and nonmalignant groups (Fig.…”