RNA Editing in Glioma as a Sexually Dimorphic Prognostic Factor That Affects mRNA Abundance in Fatty Acid Metabolism and Inflammation Pathways

RNA editing alters the nucleotide sequence and has been associated with cancer progression. However, little is known about its prognostic and regulatory roles in glioma, one of the most common types of primary brain tumors. We characterized and analyzed RNA editomes of glioblastoma and isocitrate dehydrogenase mutated (IDH-MUT) gliomas from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas (CGGA). We showed that editing change during glioma progression was another layer of molecular alterations and that editing profiles predicted the prognosis of glioblastoma and IDH-MUT gliomas in a sex-dependent manner. Hyper-editing was associated with poor survival in females but better survival in males. Moreover, noncoding editing events impacted mRNA abundance of the host genes. Genes associated with inflammatory response (e.g., EIF2AK2, a key mediator of innate immunity) and fatty acid oxidation (e.g., acyl-CoA oxidase 1, the rate-limiting enzyme in fatty acid β-oxidation) were editing-regulated and associated with glioma progression. The above findings were further validated in CGGA samples. Establishment of the prognostic and regulatory roles of RNA editing in glioma holds promise for developing editing-based therapeutic strategies against glioma progression. Furthermore, sexual dimorphism at the epitranscriptional level highlights the importance of developing sex-specific treatments for glioma.