m⁶A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas

N6-methyladenosine (m⁶A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m⁶A RNA methylation regulators ("writers", "erasers" and "readers"). Here, we demonstrate that most of the thirteen main m⁶A RNA methylation regulators are differentially expressed among gliomas stratified by different clinicopathological features in 904 gliomas. We identified two subgroups of gliomas (RM1/2) by applying consensus clustering to m⁶A RNA methylation regulators. Compared with the RM1 subgroup, the RM2 subgroup correlates with a poorer prognosis, higher WHO grade, and lower frequency of IDH mutation. Moreover, the hallmarks of epithelial-mesenchymal transition and TNFα signaling via NF-κB are also significantly enriched in the RM2 subgroup. This finding indicates that m⁶A RNA methylation regulators are closely associated with glioma malignancy. Based on this finding, we derived a risk signature, using seven m⁶A RNA methylation regulators, that is not only an independent prognostic marker but can also predict the clinicopathological features of gliomas. Moreover, m⁶A regulators are associated with the mesenchymal subtype and TMZ sensitivity in GBM. In conclusion, m⁶A RNA methylation regulators are crucial participants in the malignant progression of gliomas and are potentially useful for prognostic stratification and treatment strategy development.