Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma

Jin-Shuai Guo; Hao Ding; Peng-Yu Wu; Zi-Yi Xin; Jian-Xin Li; Hyon-Su Jo; Zhen-Hai Ma

doi:10.24920/004223

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Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma

Chinese Medical Sciences Journal Vol. 38, Issue 3, Pages: 191-205(2023)

Original Article | Updated：2024-11-26

- Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma
- Affiliations：
  
  1. 1Department of Breast Surgery, Breast Cancer Key Lab of Dalian, the Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, China
  2. 2Department of General Surgery, the Hospital of Pyongyang Medical University, D.P.R. Korea
- Author bio：
- Funds：
- DOI：10.24920/004223
  CLC：
- Received：16 March 2023，
  
  Accepted：2023-6-12，
  
  Published Online：10 July 2023，
  
  Published：30 September 2023
- Accepted：
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Jin-Shuai Guo, Hao Ding, Peng-Yu Wu, et al. Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma[J]. Chinese medical sciences journal, 2023, 38(3): 191-205.
DOI：

Jin-Shuai Guo, Hao Ding, Peng-Yu Wu, et al. Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma[J]. Chinese medical sciences journal, 2023, 38(3): 191-205. DOI： 10.24920/004223.

摘要

目的

肾透明细胞癌（kidney renal clear cell carcinoma，KIRC）是最常见的肾恶性肿瘤之一，死亡率较高。铜死亡是一种新的细胞死亡形式，通过蛋白质脂质化导致蛋白质毒性应激反应和细胞死亡。目前，很少有研究能够充分解释铜死亡相关基因（cuproptosis-related genes，CRGs）在KIRC发生发展中的潜在作用。

方法

利用来自The Cancer Genome Atlas（TCGA）数据库中的KIRC患者的RNA测序数据和相应的临床信息筛选差异表达的CRGs。通过单因素、多因素Cox比例回归分析和LASSO Cox 回归分析构建预后风险模型。使用来自Gene Expression Omnibus（GEO）数据库的数据验证模型。采用Kaplan-Meier（KM）分析和受试者工作特征（ROC）曲线来预测KIRC患者的预后。利用功能富集分析来探索其内部机制。采用单样本基因集富集分析（single-sample gene set enrichment analysis，ssGSEA）、肿瘤免疫功能障碍和排斥（Tumour Immune Dysfunction and Exclusion，TIDE）评分和药物敏感性分析进行免疫相关功能分析。

结果

我们建立了一个由4个CRGs（

DBT

、

DLAT

、

LIAS

和

PDHB

）组成的预后风险模型来预测KIRC患者的总生存期（overall survival，OS）。生存分析的结果显示，与低风险组患者相比，高风险组患者的OS显著降低。KIRC患者的1、3、5年的ROC曲线下面积（AUC）分别为0.691、0.618和0.614。功能富集分析表明，CRGs在三羧酸循环相关过程和代谢相关途径中显著富集。索拉非尼、阿霉素、恩贝酸和长春瑞滨对高风险组的患者敏感性更高。

结论

我们构建了一个简洁有效的CRGs风险模型来评估KIRC患者的预后，这可能为KIRC提供一个新的诊断和治疗方向。

Abstract

Background

Kidney renal clear cell carcinoma (KIRC) is one of the most common renal malignancies with a high mortality rate. Cuproptosis

a novel form of cell death

is strongly linked to mitochondrial metabolism and is mediated by protein lipoylation

leading to a proteotoxic stress response and cell death. To date

few studies have ellucidated the holistic role of cuproptosis-related genes (CRGs) in the pathogenesis of KIRC.

Methods

We comprehensively and completely analyzed the RNA sequencing data and corresponding clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We screened for differentially expressed CRGs and constructed a prognostic risk model using univariate and multivariate Cox proportional regression analyses. Kaplan-Meier analysis was performed and receiver operating characteristic (ROC) curves were plotted to predict the prognosis of KIRC patients. Functional enrichment analysis was utilized to explore the internal mechanisms. Immune-related functions were analyzed using single-sample gene set enrichment analysis (ssGSEA)

tumour immune dysfunction and exclusion (TIDE) scores

and drug sensitivity analysis.

Results

We established a concise prognostic risk model consisting of four CRGs (DBT

DLAT

LIAS and PDHB) to predict the overall survival (OS) in KIRC patients. The results of the survival analysis indicated a significantly lower OS in the high-risk group as compared to the patients in the low-risk group. The area under the time-dependent ROC curve (AUC) at 1

and 5 year was 0.691

0.618

and 0.614 in KIRC. Functional enrichment analysis demonstrated that CRGs were significantly enriched in tricarboxylic acid (TCA) cycle-related processes and metabolism-related pathways. Sorafenib

doxorubicin

embelin

and vinorelbine were more sensitive in the high-risk group.

Conclusions

We constructed a concise CRGs risk model to evaluate the prognosis of KIRC patients and this may be a new direction for the diagnosis and treatment of KIRC.

关键词

Keywords

references

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