Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Genes (Basel). 2022 May 10;13(5):851. doi: 10.3390/genes13050851.
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, which is characterized by metabolic reprogramming. Cuproptosis, a novel form of cell death, is highly linked to mitochondrial metabolism and mediated by protein lipoylation. However, the clinical impacts of cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In the current study, we systematically evaluated the genetic alterations of cuproptosis-related genes in ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 and PDHB exhibited differential expression between ccRCC and normal tissues (|log2(fold change)| > 2/3 and p < 0.05). Utilizing an iterative sure independence screening (SIS) method, we separately constructed the prognostic signature of CRGs for predicting the overall survival (OS) and progression-free survival (PFS) in ccRCC patients. The prognostic score of CRGs yielded an area under the curve (AUC) of 0.658 and 0.682 for the prediction of 5-year OS and PFS, respectively. In the Kaplan−Meier survival analysis of OS, a higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01−3.68), log-rank p = 1.76 × 10−7). Patients with a higher risk had a significantly shorter PFS (HR = 2.83 (2.08−3.85), log-rank p = 3.66 × 10−7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, suggesting that CDKN2A (log2(fold change) = 1.46, 95%CI: 1.75−2.35) showed significantly higher expression in ccRCC tissues while DLAT (log2(fold change) = −0.54, 95%CI: −0.93−−0.15) and FDX1 (log2(fold change) = −1.01, 95%CI: −1.61−−0.42) were lowly expressed. The expression of CDKN2A and FDX1 in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 × 10−8; FDX1: r = −0.17, p = 1.37 × 10−4). In conclusion, the cuproptosis-related gene signature could serve as a potential prognostic predictor for ccRCC patients and may offer novel insights into the cancer treatment.
透明细胞肾细胞癌（ccRCC）是最常见的肾细胞癌亚型，其特征是代谢重编程。铜死亡是一种新的细胞死亡形式，与线粒体代谢高度相关，并通过蛋白质 lipoylation 介导。然而，铜死亡相关基因（CRGs）在 ccRCC 中的临床影响在很大程度上仍不清楚。在本研究中，我们系统地评估了 ccRCC 中铜死亡相关基因的遗传改变。我们的结果表明，CDKN2A、DLAT、DLD、FDX1、GLS、PDHA1 和 PDHB 在 ccRCC 与正常组织之间表现出差异表达（|log2(fold change)|>2/3，p<0.05）。利用迭代稳健独立性筛选（SIS）方法，我们分别构建了用于预测 ccRCC 患者总生存期（OS）和无进展生存期（PFS）的 CRG 预后特征。CRGs 预后评分在预测 5 年 OS 和 PFS 方面的 AUC 分别为 0.658 和 0.682。在 OS 的 Kaplan-Meier 生存分析中，较高的铜死亡相关基因特征风险评分与较差的总生存率显著相关（HR=2.72（2.01-3.68），对数秩检验 p=1.76×10−7）。具有较高风险的患者 PFS 明显缩短（HR=2.83（2.08-3.85），对数秩检验 p=3.66×10−7）。收集了两个独立的验证数据集（GSE40435（N=101），GSE53757（N=72））进行荟萃分析，提示 CDKN2A（log2(fold change)=1.46，95%CI：1.75-2.35）在 ccRCC 组织中表达显著升高，而 DLAT（log2(fold change)=-0.54，95%CI：-0.93-−0.15）和 FDX1（log2(fold change)=-1.01，95%CI：-1.61-−0.42）表达水平较低。CDKN2A 和 FDX1 在 ccRCC 中的表达也与免疫浸润水平和程序性细胞死亡蛋白 1（PD-1）表达显著相关（CDKN2A：r=0.24，p=2.14×10−8；FDX1：r=-0.17，p=1.37×10−4）。总之，铜死亡相关基因特征可作为 ccRCC 患者潜在的预后预测指标，并可能为癌症治疗提供新的思路。
