5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer.
5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer.
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5mC调节剂介导的分子亚型描绘了肿瘤微环境的特征并指导膀胱癌的精准医疗
DOI：
10.1186/s12916-021-02163-6
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发表时间：
2021-11-26
期刊：
影响因子：
9.3
通讯作者：
Zu X
中科院分区：
文献类型：
--
作者：
Hu J;Othmane B;Yu A;Li H;Cai Z;Chen X;Ren W;Chen J;Zu X
描述肿瘤微环境（TME）的异质性和功能特征是实现膀胱癌（BLCA）精准医疗的必要条件。尽管经典分子亚型有效地反映了TME的异质性和特征，但它们的临床应用受到几个问题的限制。在这项研究中，我们整合了湘雅队列和多个外部BLCA队列，开发了一种新的5-甲基胞嘧啶（5 mC）调节剂介导的分子亚型系统和相应的定量指标，5 mC评分。进行无监督聚类以鉴定新的5 mC调节子介导的分子亚型。应用主成分分析计算5 mC评分。然后，我们将5 mC簇（5 mC评分）与BLCA中的经典分子亚型、免疫表型、临床结局和治疗机会相关联。最后，我们对5 mC评分进行了泛癌分析。鉴定出两个5 mC簇，包括5 mC簇1和簇2。这些新的5 mC簇（5 mC评分）可以准确预测BLCA的经典分子亚型、免疫表型、预后和治疗机会。5 mC簇1（高5 mC评分）指示管腔亚型和非炎症表型，其特征在于较低的抗癌免疫但较好的预后。此外，5 mC聚类1（高5 mC评分）预测对癌症免疫治疗、新辅助化疗和放疗的敏感性较低，但对抗血管生成治疗和靶向治疗（如阻断β-连环蛋白、FGFR 3和PPAR-γ通路）的敏感性较高。这种新型的基于5 mC调节子的亚型系统反映了BLCA生物学的许多方面，并为BLCA的精准医学提供了新的见解。此外，5 mC评分可能是泛癌免疫治疗反应和预后的一个可推广的预测因子。在线版本包含补充材料，可通过10.1186/s12916-021-02163-6获得。
Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers. The online version contains supplementary material available at 10.1186/s12916-021-02163-6.
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