背景:大多数人类基因具有不同的转录同工型,这主要是由3个末端的交替裂解和聚腺苷酸化(APA)引起的。N7-甲基鸟苷(m7G)也是5'末端的重要表观遗传修饰。然而,这两种RNA修饰对发育的贡献,预后,调节机制,胃癌(GC)的药物敏感性尚不清楚。
方法:从12个队列中提取2412例患者的表达数据,并使用无监督聚类方法将20个标记基因的RNA修饰模式系统地鉴定为表型聚类。在此之后,我们建立了一个RNA修饰模型(RMscore)来量化每个GC患者的RNA修饰指数。最后,我们检查了RMscore与临床特征(如生存结局)之间的相关性,亚洲癌症研究小组(ACRG)鉴定的分子亚型,转录后调控,和GC的化疗敏感性。
结果:根据RMscore将样本分为两组:高和低。RM评分低的组预后不良。此外,低RMscore与KRAS有关,刺猬,EMT,和TGF-β信号,而高RM评分与异常的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网络的调节。药物敏感性分析表明,RMscore与某些抗癌药物的反应有关。
结论:RMscore模型有可能成为GC患者预后预测的有用工具。对APA-RNA和m7G-RNA修饰的全面研究可能揭示了对GC表观遗传学的新见解,并有助于开发更有效的治疗策略。
Most human genes have diverse transcript isoforms, which mainly arise from alternative cleavage and polyadenylation (APA) at 3\' ends. N7-methylguanosine (m7 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 m7 G-RNA modifications may reveal novel insights into the epigenetics of GC and aid in the development of more effective treatment strategies.