Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personized Medicine, Nanjing Medical University, Nanjing, 211166, China.
Sci China Life Sci. 2022 Jan;65(1):19-32. doi: 10.1007/s11427-020-1928-0. Epub 2021 May 27.
Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.
腺嘌呤到肌苷（A-to-I）RNA 编辑是一种广泛存在的转录后修饰，已被证明在肿瘤发生中发挥重要作用。在这里，我们评估了来自我们南京肺癌队列（NJLCC）的 80 例肺腺癌（LUAD）患者组织中的总共 19,316 个 RNA 编辑位点，以及来自 TCGA 数据库的 486 例 LUAD 患者。肿瘤组织中的全局 RNA 编辑水平显著增加，并且在患者之间高度异质。肿瘤中高 RNA 编辑水平归因于 RNA（ADAR1 表达）和 DNA 改变（突变负荷）。基于 RNA 编辑位点的共识聚类揭示了一个新的分子亚型（EC3），与 LUAD 患者的最差预后相关。重要的是，新分类独立于基于基因表达或 DNA 甲基化的经典分子亚型。我们进一步提出了一个简化模型，包括八个 RNA 编辑位点，以准确区分我们患者中的 EC3 亚型。该模型在 TCGA 数据集进一步得到验证，曲线下面积（AUC）为 0.93（95%CI：0.91-0.95）。此外，我们发现具有 EC3 亚型的 LUAD 细胞系对四种化疗药物敏感。这些发现强调了 RNA 编辑事件在 LUAD 肿瘤发生中的重要性，并为 RNA 编辑在癌症的分子亚型和临床治疗中的应用提供了新的思路。
