多组学分析揭示了铜死亡在透明细胞肾细胞癌中的临床、免疫和药物基因组学意义。

Multi-omics analysis uncovers clinical, immunological, and pharmacogenomic implications of cuproptosis in clear cell renal cell carcinoma.

机构信息

The Fifth Hospital of Xiamen, Xiamen, 361101, Fujian, People's Republic of China.

出版信息

Eur J Med Res. 2023 Jul 22;28(1):248. doi: 10.1186/s40001-023-01221-4.

DOI:10.1186/s40001-023-01221-4

PMID:37481601

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10362584/

Abstract

OBJECTIVE

The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective.

METHODS

This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation.

RESULTS

Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients' survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group.

CONCLUSION

Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

摘要

目的

最新研究提出了一种新型的铜依赖性程序性细胞死亡，命名为铜死亡。我们旨在从多组学的角度阐明铜死亡在透明细胞肾细胞癌（ccRCC）中的影响。

方法

本研究系统评估了 TCGA ccRCC 样本中铜死亡基因的 mRNA 表达、甲基化和遗传改变。通过无监督聚类分析，将样本分为不同的铜死亡亚型，在 E-MTAB-1980 数据集通过 NTP 方法验证。接下来，基于铜死亡相关基因通过 PCA 计算铜死亡评分（Cuscore）。我们还评估了临床和免疫基因组特征、药物敏感性、免疫治疗反应和转录后调控。

结果

铜死亡基因在 ccRCC 中存在多层次改变，并与患者的生存和免疫微环境有关。我们定义了三种铜死亡亚型[C1（中度铜死亡）、C2（低度铜死亡）和 C3（高度铜死亡）]，并进一步证明了这种分类的稳健性和可重复性。总体生存情况在 C3 中最好，在 C1 中中等，在 C2 中最差。C1 对帕唑帕尼和索拉非尼最敏感，而 C2 对舒尼替尼最敏感。此外，C1 患者从抗 PD-1 免疫治疗中获益更多。Cuscore 高的患者表现出显著的生存优势。Cuscore 与免疫基因组特征和有助于 ccRCC 发展的转录后事件高度相关。最后，为低 Cuscore 组选择了几种潜在的化合物和可药物靶标（NMU、RARRES1）。