DNA methylation profiling identifies long-range epigenetic silencing of clustered protocadherins as a key determinant of meningioma progression.

Meningioma is the most common primary brain tumour in adults. However, molecular drivers of progression occurring in a subset of meningiomas are poorly understood. We hypothesise that epigenomic variations are causal for the clinical heterogeneity of meningiomas and may be functionally relevant for disease progression. To test this hypothesis, we perform global DNA methylation profiling of a large cross-sectional cohort and a longitudinal cohort of human meningiomas. Our analysis identifies a DNA hypermethylation signature that is correlated with clinical outcomes and enables more accurate prognostication for meningiomas than previous classification systems. Analyses of longitudinal high-grade meningioma samples in comparison to clinically benign meningiomas and normal meningeal tissue show convergent contributions but differing plasticity of copy number variations and DNA hypermethylation along the trajectory of meningioma progression. Systematic analysis of DNA hypermethylation in high-grade meningiomas unravels a tumour suppressive role of clustered protocadherins by restricting β-catenin nuclear localisation, consistent with the association between nuclear β-catenin staining and meningioma progression. Together, our study provides fundamental insights into the molecular mechanisms underlying the heterogeneity of clinically benign and aggressive meningiomas and the microevolutionary adaptation during disease progression.