Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Neurology, The First Hospital of China Medical University, Shenyang, China.
Cancer Med. 2023 Jan;12(1):879-897. doi: 10.1002/cam4.4861. Epub 2022 May 30.
Most human genes have diverse transcript isoforms, which mainly arise from alternative cleavage and polyadenylation (APA) at 3' ends. N7-methylguanosine (m G) is also an essential epigenetic modification at the 5' end. However, the contribution of these two RNA modifications to the development, prognosis, regulation mechanisms, and drug sensitivity of gastric cancer (GC) is unclear.
The expression data of 2412 patients were extracted from 12 cohorts and the RNA modification patterns of 20 marker genes were systematically identified into phenotypic clusters using the unsupervised clustering approach. Following that, we developed an RNA modification model (RMscore) to quantify each GC patient's RNA modification index. Finally, we examined the correlation between RMscore and clinical features such as survival outcomes, molecular subtypes identified by the Asian Cancer Research Group (ACRG), posttranscriptional regulation, and chemotherapeutic sensitivity in GC.
The samples were categorized into two groups on the basis of their RMscore: high and low. The group with a low RMscore had a bad prognosis. Moreover, the low RMscore was associated with KRAS, Hedgehog, EMT, and TGF-β signaling, whereas a high RMscore was related to abnormal cell cycle signaling pathway activation. The findings also revealed that the RMscore contributes to the regulation of the miRNA-mRNA network. Drug sensitivity analysis revealed that RMscore is associated with the response to some anticancer drugs.
The RMscore model has the potential to be a useful tool for prognosis prediction in patients with GC. A comprehensive investigation of APA-RNA and m G-RNA modifications may reveal novel insights into the epigenetics of GC and aid in the development of more effective treatment strategies.
大多数人类基因具有多种转录异构体，主要通过 3' 端的可变剪接和多聚腺苷酸化（APA）产生。N7-甲基鸟苷（mG）也是 5' 端的一种重要表观遗传修饰。然而，这两种 RNA 修饰对胃癌（GC）的发生发展、预后、调控机制和药物敏感性的贡献尚不清楚。
从 12 个队列中提取了 2412 名患者的表达数据，并使用无监督聚类方法系统地将 20 个标记基因的 RNA 修饰模式识别为表型聚类。之后，我们开发了一个 RNA 修饰模型（RMscore）来量化每个 GC 患者的 RNA 修饰指数。最后，我们研究了 RMscore 与临床特征（如生存结果、由亚洲癌症研究组（ACRG）确定的分子亚型、转录后调控和 GC 的化疗敏感性）之间的相关性。
根据 RMscore 将样本分为高和低两组：低 RMscore 组的预后较差。此外，低 RMscore 与 KRAS、Hedgehog、EMT 和 TGF-β 信号通路有关，而高 RMscore 与异常细胞周期信号通路激活有关。研究结果还表明，RMscore 有助于 miRNA-mRNA 网络的调控。药物敏感性分析表明，RMscore 与某些抗癌药物的反应有关。
RMscore 模型有望成为预测 GC 患者预后的有用工具。全面研究 APA-RNA 和 mG-RNA 修饰可能会为 GC 的表观遗传学提供新的见解，并有助于开发更有效的治疗策略。
