GENE-09. FUNCTIONAL GENOMIC ELEMENTS DEFINED BY DNA METHYLATION CAN DISTINGUISH MENINGIOMA SUBGROUPS

Despite advances in therapy, treatment of malignant meningioma remains challenging - the tumor usually progresses after treatment. Atypical and anaplastic (malignant) meningiomas (grades II/III) are high-risk meningiomas that are prone to recurrence and unfavorable prognosis. We seek to understand the mechanisms of meningioma progression after initial treatment. Recently, based on DNA methylation, two subgroups of meningioma were described with recurrence-free survival differences. Master regulators at distinct genomic elements define gene activity and tissue identity and deregulation have been shown to be involved in tumorigenesis. We hypothesize that functional genomic elements can contribute to meningioma progression/recurrence. Our aim is to use DNA methylation data to identify candidate noncoding elements and their connection with genes that might explain differences in meningioma prognostic subgroups. Using published DNA methylation markers that define favorable and unfavorable meningioma subgroups, we identified 1,330 differentially methylated probes (p< 0.0001, difference mean-methylation beta-value> 0.25) distributed across CpG islands (13%), shores (34%) and open-sea regions (53%). Focusing on probes within known functional genomics, we identified 18 highly conserved genomic enhancers that can potentially drive meningioma recurrence. We next investigated links between these enhancers and their targeted genes by incorporating GeneHancer annotation. We found that the unfavorable subgroup of meningiomas presented hypomethylation within enhancer regions that have the potential to target PARK7, ARID4B, and FBH1. ARID4B was previously shown to be highly active in high-grade meningiomas. Our preliminary results are the first to suggest that DNA methylation changes can be used to identify noncoding regions associated with meningioma prognosis. We will use additional independent data to confirm our preliminary results. Identification of noncoding regions associated with meningioma progression/recurrence will provide knowledge of the role of epigenomics in the development of malignant meningioma and of opportunities for targeted therapy.