Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Front Immunol. 2022 Aug 18;13:901662. doi: 10.3389/fimmu.2022.901662. eCollection 2022.
Kidney cancer is one the most lethal cancers of the urinary system, but current treatments are limited and its prognosis is poor. This study focused on kidney renal clear cell carcinoma (KIRC) and analyzed the relationship between epigenetic alterations and KIRC prognosis, and explored the prognostic significance of these findings in KIRC patients. Based on multi-omics data, differentially expressed histone-modified genes were identified using the R package limma package. Gene enhancers were detected from data in the FANTOM5 database. Gene promoters were screened using the R package ChIPseeker, and the Bumphunter in the R package CHAMP was applied to screen differentially methylated regions (DMR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis of genes was performed using the R package clusterProfiler. We identified 51 dysregulated epigenetic protein coding genes (epi-PCGs) from 872 epi-PCGs, and categorized three molecular subtypes (C1, C2, and C3) of KIRC samples with significantly different prognosis. Notably, among the three molecular subtypes, we found a markedly differential immune features in immune checkpoints, cytokines, immune signatures, and immune cell distribution. C2 subtype had significantly lower enrichment score of IFNγ, cytotoxic score (CYT), and angiogenesis. In addition, an 8-gene signature containing 8 epi-PCGs (ETV4, SH2B3, FATE1, GRK5, MALL, HRH2, SEMA3G, and SLC10A6) was developed for predicting KIRC prognosis. Prognosis of patients with a high 8-gene signature score was significantly worse than those with a low 8-gene signature score, which was also validated by the independent validation data. The 8-gene signature had a better performance compared with previous signatures of KIRC. Overall, this study highlighted the important role of epigenetic regulation in KIRC development, and explored prognostic epi-PCGs, which may provide a guidance for exploiting further pathological mechanisms of KIRC and for developing novel drug targets.
肾细胞癌是泌尿系统中最致命的癌症之一，但目前的治疗方法有限，预后较差。本研究聚焦于肾透明细胞癌（KIRC），分析了表观遗传改变与 KIRC 预后的关系，并探讨了这些发现对 KIRC 患者预后的意义。基于多组学数据，使用 R 包 limma 包识别差异表达的组蛋白修饰基因。从 FANTOM5 数据库中的数据中检测基因增强子。使用 R 包 ChIPseeker 筛选基因启动子，使用 R 包 CHAMP 中的 Bumphunter 筛选差异甲基化区域（DMR）。使用 R 包 clusterProfiler 对基因进行京都基因与基因组百科全书（KEGG）通路分析和基因本体论（GO）功能富集分析。我们从 872 个表观遗传蛋白编码基因（epi-PCGs）中鉴定出 51 个失调的表观遗传蛋白编码基因（epi-PCGs），并将 KIRC 样本分为三个具有显著不同预后的分子亚型（C1、C2 和 C3）。值得注意的是，在这三个分子亚型中，我们发现免疫检查点、细胞因子、免疫特征和免疫细胞分布方面的免疫特征存在显著差异。C2 亚型 IFNγ、细胞毒性评分（CYT）和血管生成的富集评分显著降低。此外，我们开发了一个包含 8 个 epi-PCGs（ETV4、SH2B3、FATE1、GRK5、MALL、HRH2、SEMA3G 和 SLC10A6）的 8 基因特征，用于预测 KIRC 预后。高 8 基因特征评分患者的预后明显差于低 8 基因特征评分患者，这在独立验证数据中也得到了验证。与 KIRC 的先前特征相比，8 基因特征具有更好的性能。总体而言，本研究强调了表观遗传调控在 KIRC 发生发展中的重要作用，并探索了预后 epi-PCGs，这可能为进一步探索 KIRC 的病理机制和开发新的药物靶点提供指导。
