Data_Sheet_4_Comprehensive Analysis of N6-methyladenosine Modification Patterns Associated With Multiomic Characteristics of Bladder Cancer.ZIP

Purpose: To comprehensively analyze N6-methyladenosine modification patterns in bladder tumors and to further systematically explore the inherent relationships between these modification patterns and multiomic tumor characteristics.Materials and Methods: A total of 901 bladder tumor samples, including 405 samples from TCGA database, 188 samples from GSE13507 and 308 samples from GSE32894, were included in this systematic analysis. The N6-methyladenosine modification patterns were identified utilizing unsupervised clustering analysis. To quantify N6-methyladenosine modification patterns, the m6Ascore of individual sample was developed using principal component analysis algorithms. Relationships among immune infiltration, tumor mutation burden, various clinical characteristics, molecular subtypes, and the m6Ascore were systematically analyzed. The guiding value of m6Ascore in immunotherapy was further validated in an external trial cohort. Genomics of Drug Sensitivity in Cancer expression references were also utilized to perform drug sensitivity analysis for patients with distinct m6A modification patterns.Results: We determined three different N6-methyladenosine modification patterns for 901 bladder tumors. The quantitative m6Ascore of individual sample derived from N6-methyladenosine modification patterns could play a significant role in predicting overall survival, immune cell infiltration, and classic oncogene mutations. A low m6Ascore combined with high tumor mutation burden indicated better survival outcomes (p < 0.001). A higher m6Ascore also indicated a higher grade, higher T and N stage, elder ages, higher death rate, and higher PD1/PDL1/CTLA4 expressions (p < 0.01). The Basal type tended to exhibit significantly higher m6Ascores than the Luminal and Neuronal subtypes. External immunotherapy cohorts demonstrated that no difference in therapeutic effects was noted between the high and low m6Ascore groups when anti-PD1 immunotherapy was exclusively administered. When anti-PD1 and anti-CTLA4 immunotherapy were simultaneously administered, the high m6Ascore group had a significantly better prognosis than the low m6Ascore group (p < 0.001). High m6A groups were potentially sensitive to various medical treatments including Bleomycin, Bortezomib, Cisplatin, Cyclopamine, Dasatinib, Docetaxe, Rapamycin, and Vinblastine in this study.Conclusions: This study systematically revealed the important roles of m6A methylation modification patterns in bladder tumors. Detailed quantification of m6A modification patterns could improve our understanding of the bladder tumor microenvironments and could provide guidance for future immunotherapy strategies.

目的：全面分析膀胱肿瘤中N6-甲基腺苷修饰模式的特征，并进一步系统地探究这些修饰模式与多组学肿瘤特征之间的内在联系。材料与方法：纳入901例膀胱肿瘤样本，包括来自TCGA数据库的405例样本，来自GSE13507的188例样本和来自GSE32894的308例样本，进行系统性分析。利用无监督聚类分析识别N6-甲基腺苷修饰模式。为量化N6-甲基腺苷修饰模式，开发了单个样本的m6Ascore，采用主成分分析算法。系统地分析了免疫浸润、肿瘤突变负荷、各种临床特征、分子亚型和m6Ascore之间的关系。在外部临床试验队列中进一步验证了m6Ascore在免疫治疗中的指导价值。同时，利用癌症药物敏感性基因组学表达参考进行了具有不同m6A修饰模式患者的药物敏感性分析。结果：我们确定了901例膀胱肿瘤中的三种不同的N6-甲基腺苷修饰模式。从N6-甲基腺苷修饰模式中得到的单个样本的m6Ascore在预测总生存期、免疫细胞浸润和经典癌基因突变方面发挥重要作用。低m6Ascore与高肿瘤突变负荷相结合，表明更好的生存结果（p < 0.001）。较高的m6Ascore还表明更高的分级、更高的T和N期、更老年龄、更高的死亡率以及更高的PD1/PDL1/CTLA4表达（p < 0.01）。基底型倾向于比管腔型和神经元亚型表现出显著更高的m6Ascore。外部免疫治疗队列显示，当仅给予抗PD1免疫治疗时，高m6Ascore组和低m6Ascore组之间未见治疗效果的差异。当同时给予抗PD1和抗CTLA4免疫治疗时，高m6Ascore组比低m6Ascore组具有显著更好的预后（p < 0.001）。本研究中，高m6A组对多种药物治疗（如博来霉素、硼替佐米、顺铂、环孢素、达沙替尼、多西他赛、雷帕霉素和长春碱）可能敏感。结论：本研究系统地揭示了m6A甲基化修饰模式在膀胱肿瘤中的重要角色。m6A修饰模式的详细量化能够加深我们对膀胱肿瘤微环境的理解，并为未来的免疫治疗策略提供指导。