Ye Fangdie, Liang Yingchun, Hu Jimeng, Hu Yun, Liu Yufei, Cheng Zhang, Ou Yuxi, Xu Chenyang, Jiang Haowen
Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
Front Cell Dev Biol. 2021 Dec 3;9:760369. doi: 10.3389/fcell.2021.760369. eCollection 2021.
Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy. We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis. Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses. Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.
考虑到膀胱癌中表观遗传调控的异质性和复杂性，必须研究免疫微环境中整体DNA甲基化修饰的潜在机制，以预测预后结果和免疫治疗的临床反应。我们使用无监督聚类算法系统地评估了985个整合的膀胱癌样本的DNA甲基化模式。随后，分析了这些DNA甲基化模式与免疫微环境特征的相关性。采用主分析算法计算每个样本的DMR分数进行资格分析。在985个膀胱癌样本中发现了三种DNA甲基化模式，这些模式与不同的临床结果和几种免疫微环境表型相关，例如免疫沙漠型、免疫炎症型和免疫排除型。然后根据基于DNA甲基化相关基因（DMRGs）表达计算的DMR分数，将患者分为高DMR分数亚组和低DMR分数亚组。低DMR分数亚组的患者具有显著的生存优势，这与免疫炎症表型显著相关。进一步分析表明，低DMR分数的患者TP53野生型突变较少，癌症分期较低，分子亚型主要为乳头状亚型。此外，一个独立的免疫治疗队列证实，DMR分数可以作为预测预后结果和免疫反应的标志物。整体DNA甲基化模式可用于预测膀胱癌的免疫表型、侵袭性和免疫反应。DNA甲基化状态评估将加强我们对免疫微环境特征的认识，并促进更有效治疗策略的发展。
