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 that RBM15B expression 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 high RBM15B expression. 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.

中文翻译：

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m6A RNA甲基化调节剂的表达谱分析表明，它们与免疫相关，可以预测肾肾细胞癌的生存

N6-甲基腺苷（m6A）是指发生在腺苷的氮-6位的甲基化修饰。许多人类生理过程，例如精子发生的调节是由m6A RNA修饰引起的。但是，仍很少研究m6A RNA甲基化调节剂与肾肾透明细胞癌（KIRC）之间的关系。这项工作旨在探讨KIRC中m6A RNA甲基化调节剂的影响。我们检查了KIRC不同临床病理特征之间异常表达的m6A RNA甲基化调节剂。我们认识到三个亚组（KIRC1，KIRC2和KIRC3）通过m6A RNA甲基化调节因子的共有簇在总体存活率上存在显着差异。令人惊讶的是，KIRC2显示出较高的免疫活性，但是基于单样本基因集富集分析（ssGSEA）和CIBERSORT分析，免疫抑制细胞（Tregs和髓样来源的抑制细胞）比例很高。此外，KIRC2亚组的肿瘤突变负荷水平最低，而共抑制分子的最高表达水平为80％（12/15）。接下来，相关分析表明ssGSEA和CIBERSORT分析证实了RBM15B表达与多个免疫特征呈负相关。高RBM15B组丰富了多种免疫相关和癌症相关途径表达。此外，基于ArrayExpress（E-MTAB-3267）数据集构建了基于4 m6A RNA甲基化调节剂的风险信号，并在癌症基因组图谱（TCGA）测试队列中得到了证实。总之，我们的研究成功地将TCGA样品分为具有不同免疫特征的三个亚组，并提示KIRC2的不良预后可能是由免疫逃避引起的。这些发现将有助于KIRC患者的个性化免疫治疗。此外，风险评分系统被揭示为可以预测KIRC患者生存的独立预后指标。