DNA Methylation Signatures Differentiate Meningiomas from Normal Dura [HumanMethylation450]. DNA Methylation Signatures Differentiate Meningiomas from Normal Dura [HumanMethylation450]

Meningiomas are the most common primary brain tumor. Though typically benign with a low mutational burden, histopathologic analysis has poor predictive value for malignant behavior and there are no proven chemotherapies. Although DNA methylation patterns distinguish subgroups of meningiomas and have higher predictive value for tumor behavior than histologic classification, little is known about differences in DNA methylation between meningiomas and surrounding normal dura tissue. Using multimodal studies of meningioma/dura pairs, we identified 4 distinct DNA methylation patterns. Diffuse DNA hypomethylation of malignant meningiomas readily facilitated their identification from lower grade tumors by unsupervised clustering. All clusters and 12/12 meningioma-dura pairs exhibited hypomethylation of the gene promoters of a module associated with the craniofacial patterning transcription factor FOXC1 and its upstream lncRNA FOXCUT. Furthermore, we identified an epigenetic continuum of increasing hypermethylation of polycomb repressive complex target promoters with increased histopathologic grade suggesting progressive epigenetic dysregulation is associated with increasing tumor aggressiveness. These findings are a starting point for future investigations of the role of epigenetic dysregulation of FOXC1 and cranial patterning genes in early stages of meningioma formation as well as studies of the utility of polycomb inhibitors for treatment of aggressive meningiomas. Overall design: DNA methylation of matched meningioma/dura samples from 12 patients (11 WHO grade I, 1 WHO grade II) and 19 meningiomaswere assessed using Illumina HM450K methylation arrays. Also analyzed including were DNA methylation array data from 19 meningiomas (11 WHO grade I, 6 WHO grade II, and 4 WHO grade III) previously reported in GEO (GSE42882).