Research Paper Volume 11, Issue 4 pp 1204—1225

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

Rui-Chao Chai 1, 3, 5, *, , Fan Wu 1, 5, *, , Qi-Xue Wang 4, 5, *, , Shu Zhang 4, , Ke-Nan Zhang 1, 5, , Yu-Qing Liu 1, 5, , Zheng Zhao 1, 5, , Tao Jiang 1, 2, 3, 5, , Yong-Zhi Wang 1, 2, 3, 5, , Chun-Sheng Kang 4, 5, 6, ,

  • 1 Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing 100160, China
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100160, China
  • 3 China National Clinical Research Center for Neurological Diseases, Beijing, China
  • 4 Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China
  • 5 Chinese Glioma Genome Atlas Network (CGGA)
  • 6 Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
* Equal contribution

received: December 18, 2018 ; accepted: February 12, 2019 ; published: February 27, 2019 ;

https://doi.org/10.18632/aging.101829
How to Cite

Copyright: Chai et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Abstract

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.

Abbreviations

Long noncoding RNAs: lncRNAs; micro-RNA: miRNA; N6,2’-O-dimethyladenosine: (m6A); Methyltransferase-Like 3: METTL3; Wilms Tumor 1-Associated Protein: WTAP); domain-containing protein 13: ZC3H13; obesity-associated protein: FTO; α-ketoglutarate-dependent dioxygenase alkB homolog 5: ALKBH5; the Chinese Glioma Genome Atlas: CGGA; The Cancer Genome Atlas: TCGA; 1p/19q codeletion: 1p/19q codel; glioblastoma: GBM; principal component analysis: PCA; Gene Ontology: GO; Kyoto Encyclopedia of Genes and Genomes: KEGG; Gene Set Enrichment Analysis: GSEA; the least absolute shrinkage and selection operator: LASSO; receiver operating characteristic: ROC; overall survival: OS; acute myelocytic leukemia: AML.