Expression Profile Analysis of m6A RNA Methylation Regulators Indicates They Are Immune Signature Associated and Can Predict Survival in Kidney Renal Cell Carcinoma
Expression Profile Analysis of m6A RNA Methylation Regulators Indicates They Are Immune Signature Associated and Can Predict Survival in Kidney Renal Cell Carcinoma
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DOI：
10.1089/dna.2020.5767
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发表时间：
2020-10-20
影响因子：
3.1
通讯作者：
Li, Huixiang
中科院分区：
文献类型：
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作者：
Fang, Jiuyuan;Hu, Mingyang;Li, Huixiang
N6-甲基腺苷（m6 A）是指在腺苷的氮-6位发生的甲基化修饰。许多人类生理过程，如精子发生的调节是由m6 A RNA修饰引起的。然而，m6 A RNA甲基化调节剂与肾透明细胞癌（KIRC）之间的关系仍然很少调查。本研究旨在探讨m6 A RNA甲基化调节因子对KIRC的影响。我们研究了KIRC不同临床病理特征中异常表达的m6 A RNA甲基化调节因子。我们通过m6 A RNA甲基化调节子的一致聚类，识别出总生存率有显著差异的三个亚组（KIRC 1、KIRC 2和KIRC 3）。令人惊讶的是，基于单样本基因集富集分析（ssGSEA）和CIBERSORT分析，KIRC 2显示出升高的免疫活性，但高比例的免疫抑制细胞（THBG和骨髓来源的抑制细胞）。此外，KIRC 2亚组具有最低的肿瘤突变负荷水平和80%（12/15）的共抑制分子的最高表达水平。相关性分析表明RBM 15 B表达与多种免疫特征呈负相关，并通过ssGSEA和CIBERSORT分析得到验证。在RBM 15 B高表达组中，多个免疫相关和癌症相关通路富集。此外，基于ArrayExpress（E-MTAB-3267）数据集构建了基于四m6 A RNA甲基化调节剂的风险特征，并在癌症基因组图谱（TCGA）测试队列中得到证实。总之，我们的研究成功地将TCGA样本分为三个具有不同免疫特征的亚组，并表明KIRC 2的不良预后可能是由免疫逃避介导的。这些发现将促进KIRC患者的个性化免疫治疗。此外，风险评分系统被认为是一个独立的预后指标，可以预测KIRC患者的生存。
N6-Methyladenosine (m6A) refers to the methylation modification occurring at the nitrogen-6 position of adenosine. Many human physiological processes such as modulation of spermatogenesis are caused by m6A RNA modifications. However, the relationship between m6A RNA methylation regulators and kidney renal clear cell carcinoma (KIRC) remains rarely investigated. This work aimed to explore the influence of m6A RNA methylation regulators in KIRC. We examined abnormally expressed m6A RNA methylation regulators among different clinicopathological features of KIRC. We recognized three subgroups (KIRC1, KIRC2, and KIRC3) with significant differences in overall survival through consensus clustering of m6A RNA methylation regulators. Surprisingly, KIRC2 displayed elevated immune activity, but high proportions of immune-inhibitory cells (Tregs and myeloid-derived suppressor cell) based on single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT analysis. Moreover, the KIRC2 subgroup had the lowest tumor mutation burden levels and the highest expression levels of 80% (12/15) of co-inhibitory molecules. Next, correlation analysis indicated thatRBM15Bexpression was negatively correlated with multiple immune signatures, which was verified by ssGSEA and CIBERSORT analyses. Multiple immune-related and cancer-related pathways were enriched in the group with highRBM15Bexpression. Furthermore, a four-m6A RNA methylation regulator-based risk signature was constructed based on an ArrayExpress (E-MTAB-3267) dataset and confirmed in the The Cancer Genome Atlas (TCGA) testing cohort. In conclusion, our study successfully classified TCGA samples into three subgroups with different immune signatures, and suggested that the worse prognosis of KIRC2 is probably mediated by immune evasion. These findings will facilitate personalized immunotherapy in patients with KIRC. In addition, the risk score system was revealed as an independent prognostic marker that can predict survival in KIRC patients.