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

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.

MicroRNAs miR-16 and miR-519 control meningioma cell proliferation via overlapping transcriptomic programs shared with the RNA-binding protein HuR

“…In this regard, the restricted 208-gene signature deserves attention as many of these genes ( Table S8 ) may emerge as precious additions to the meningioma biomarker repertoire. Moreover, many targets genes and signatures proposed by the transcriptomics (HuR, HIF1A and hypoxia, EP300) have already been functionally validated or meta-analytically cross-validated in previous works ( 11 , 43 , 61 ). In a previous study on HuR in meningioma patients and following knockdown in the same meningioma cell lines, we already correlated mRNA and protein levels, as well as HuR cellular localization and post-translational modifications.…”

“…Hypoxia being under the tight control of HIF1A, we demonstrated it to be a hallmark of meningioma progression. Concerning the transcription factor EP300, we previously correlated a methylation signature with grade, progression, and proliferation markers such as Ki-67 and MCM6 and showed that the regulatory regions associated with meningioma growth are highly enriched in CpG islands located in enhancers in distal regions ( 61 ). This methylation signature is known to be a mark of tissue-specific EP300 activity, and involved in cell growth and division in cancers ( 62 , 63 ).…”

“…DNA methylation may also participate in the inhibition of certain miR-related gene transcription ( 73 ). For example, our group recently described methylation of miR-16-linked regulatory regions as being strongly correlated with proliferation markers and indices ( 61 ). It remains unclear, however, what causes the downregulation of miR-519 in meningiomas.…”

CARCINOGENICITY OF IONIZING RADIATION: A LITERATURE REVIEW

“…Потеря метилирования по всему геному, особенно в повторяющихся элементах [16], способствует развитию новообразований желудочно-кишечного тракта и считается основным признаком рака [17,18]. Было подсчитано, что более 300 генов и генных продуктов оказываются эпигенетически изменены при различных видах рака у человека [19]. Метаанализ измененных генов при колоректальном раке подтверждает их участие в онкогенезе [20].…”

DNA methylation meningioma biomarkers: attributes and limitations

“…Nonetheless, meningiomas are largely histomorphology and varieties are unlimited, such as the degree of mitotic activity, brain invasion, and aggressive histologic activities. Current WHO classifications of meningiomas are limited to predict benign tumors and aggressive ones, and fail to precisely foretell the clinical performance, aggressiveness, and long-period recurrence of specific meningiomas ( Hergalant et al, 2022 ).…”