Pan-cancer analysis of ADAR1 with its prognostic relevance in low-grade glioma

Abstract

ADAR1, known as the primary enzyme for adenosine-to-inosine RNA editing, has recently been implicated in cancer development through both RNA editing-dependent and −independent pathways. These discoveries suggest that ADAR1′s functions may extend beyond our current understanding. A pan-cancer analysis offers a unique opportunity to identify both common and distinct mechanisms across various cancers, thereby advancing personalized medicine. Low-grade glioma (LGG), characterized by a diverse group of tumor cells, presents a challenge in risk stratification, leading to significant variations in treatment approaches. Recently discovered molecular alterations in LGG have helped to refine the stratification of of these tumors and offered novel targets for predicting likely outcomes. This study aims to provide a detailed analysis of ADAR mRNA across multiple cancers, emphasizing its prognostic significance in LGG. We observed inconsistent mRNA and consistent protein expression patterns of ADAR1/ADAR in pan-cancer analyses that across tumor types. ADAR mRNA expression did not always correlate with ADAR1 protein expression. Nevertheless, the transcript levels correlated significantly with genetic alterations, tumor mutation burden, microsatellite instability, overall survival, recurrence-free survival, immune marker presence, immune infiltration, and the survival of patients undergoing immunotherapy in select cancers. Furthermore, ADAR and its top 50 associated genes were primarily involved in mRNA-related events, as identified through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Utilizing the Cox proportional hazards model, we developed a 3-gene signature (ADAR, HNRNPK, and SMG7), which effectively stratified patients into high- and low-risk groups, with high-risk patients exhibiting poorer overall survival, higher tumor grades, and a greater number of non-codeletions. Overall, this signature was inversely related to immune infiltration across cancers. Transcription factor SPI1 and miR-206, potential upstream regulators of the signature genes, were closely linked to patient survival in LGG. The promoter regions of these genes were hypermethylated, further associating them with patient outcomes. Additionally, these genes displayed consistent drug susceptibility patterns. In conclusion, our findings reveal multiple aspects of ADAR1′s role in cancer and underscore its prognostic value in LGG, offering insights into potential therapeutic targets and strategies.