Correlation between DNA Methylation and Cell Proliferation Identifies New Candidate Predictive Markers in Meningioma

SIMPLE SUMMARY: In adults, meningioma is the most common primary tumor of the brain. It is classified into three clinical grades of aggressiveness. Whereas disease recurrence after surgery and survival are associated with grade, it is worth investigating proliferation at a molecular level to identify markers capable of improving the clinical management of meningioma. In this study, we explore the DNA methylation profiles of 48 tumors of various grades and conduct statistical analyses on several proliferation indices and markers, such as mitotic index, grade, and Ki-67 or MCM6 expression levels. We identify differential methylation profiles between grades, loci highly correlated with cell growth and division, and a specific methylation signature of regulatory regions persistently associated with proliferation indices, grade, and survival. Finally, we report candidate genes under the control of these regions with potential prognostic and therapeutic value and deserving clinical evaluation. ABSTRACT: Meningiomas are the most common primary tumors of the central nervous system. Based on the 2021 WHO classification, they are classified into three grades reflecting recurrence risk and aggressiveness. However, the WHO’s histopathological criteria defining these grades are somewhat subjective. Together with reliable immunohistochemical proliferation indices, other molecular markers such as those studied with genome-wide epigenetics promise to revamp the current prognostic classification. In this study, 48 meningiomas of various grades were randomly included and explored for DNA methylation with the Infinium MethylationEPIC microarray over 850k CpG sites. We conducted differential and correlative analyses on grade and several proliferation indices and markers, such as mitotic index and Ki-67 or MCM6 immunohistochemistry. We also set up Cox proportional hazard models for extensive associations between CpG methylation and survival. We identified loci highly correlated with cell growth and a targeted methylation signature of regulatory regions persistently associated with proliferation, grade, and survival. Candidate genes under the control of these regions include SMC4, ESRRG, PAX6, DOK7, VAV2, OTX1, and PCDHA-PCDHB-PCDHG, i.e., the protocadherin gene clusters. This study highlights the crucial role played by epigenetic mechanisms in shaping dysregulated cellular proliferation and provides potential biomarkers bearing prognostic and therapeutic value for the clinical management of meningioma.