Yang Qin, Li Xin
Puai Medical College, Shaoyang University, Shaoyang, Hunan, China.
Department of Immunology, School of Basic Medical of Central South University, Changsha, Hunan, China.
Immunobiology. 2024 Nov;229(6):152855. doi: 10.1016/j.imbio.2024.152855. Epub 2024 Sep 24.
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.
ADAR1作为腺苷到肌苷RNA编辑的主要酶，最近通过RNA编辑依赖和非依赖途径与癌症发展相关。这些发现表明ADAR1的功能可能超出我们目前的理解。泛癌分析为识别各种癌症中的共同和独特机制提供了独特机会，从而推动个性化医疗。低级别胶质瘤（LGG）以多种肿瘤细胞为特征，在风险分层方面存在挑战，导致治疗方法有显著差异。最近在LGG中发现的分子改变有助于完善这些肿瘤的分层，并为预测可能的结果提供了新的靶点。本研究旨在对多种癌症中的ADAR mRNA进行详细分析，强调其在LGG中的预后意义。我们在跨肿瘤类型的泛癌分析中观察到ADAR1/ADAR的mRNA表达不一致和蛋白质表达一致的模式。ADAR mRNA表达并不总是与ADAR1蛋白表达相关。然而，转录水平与基因改变、肿瘤突变负担、微卫星不稳定性、总生存期、无复发生存期、免疫标志物存在、免疫浸润以及特定癌症中接受免疫治疗患者的生存期显著相关。此外，通过基因本体论和京都基因与基因组百科全书分析确定，ADAR及其前50个相关基因主要参与mRNA相关事件。利用Cox比例风险模型，我们开发了一个三基因特征（ADAR、HNRNPK和SMG7），该特征有效地将患者分为高风险和低风险组，高风险患者的总生存期较差、肿瘤分级较高且非缺失数量较多。总体而言，该特征与癌症中的免疫浸润呈负相关。转录因子SPI1和miR-206是特征基因的潜在上游调节因子，与LGG患者的生存密切相关。这些基因的启动子区域发生高甲基化，进一步将它们与患者预后联系起来。此外，这些基因表现出一致的药物敏感性模式。总之，我们的发现揭示了ADAR1在癌症中的多个作用方面，并强调了其在LGG中的预后价值，为潜在的治疗靶点和策略提供了见解。
