A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma
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 o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/5/851 |
| _version_ | 1797499588906582016 |
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| author | Zilong Bian Rong Fan Lingmin Xie |
| author_facet | Zilong Bian Rong Fan Lingmin Xie |
| author_sort | Zilong Bian |
| collection | DOAJ |
| description | 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 <i>CDKN2A</i>, <i>DLAT</i>, <i>DLD</i>, <i>FDX1</i>, <i>GLS</i>, <i>PDHA1</i> and <i>PDHB</i> exhibited differential expression between ccRCC and normal tissues (|log<sub>2</sub>(fold change)| > 2/3 and <i>p</i> < 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 (<i>HR</i> = 2.72 (2.01–3.68), log-rank <i>p</i> = 1.76 × 10<sup>−7</sup>). Patients with a higher risk had a significantly shorter PFS (<i>HR</i> = 2.83 (2.08–3.85), log-rank <i>p</i> = 3.66 × 10<sup>−7</sup>). Two independent validation datasets (GSE40435 (<i>N</i> = 101), GSE53757 (<i>N</i> = 72)) were collected for meta-analysis, suggesting that CDKN2A (log<sub>2</sub>(fold change) = 1.46, 95%CI: 1.75–2.35) showed significantly higher expression in ccRCC tissues while DLAT (log<sub>2</sub>(fold change) = −0.54, 95%CI: −0.93–−0.15) and FDX1 (log<sub>2</sub>(fold change) = −1.01, 95%CI: −1.61–−0.42) were lowly expressed. The expression of <i>CDKN2A</i> and <i>FDX1</i> in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: <i>r</i> = 0.24, <i>p</i> = 2.14 × 10<sup>−8</sup>; FDX1: <i>r</i> = −0.17, <i>p</i> = 1.37 × 10<sup>−4</sup>). 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. |
| first_indexed | 2024-03-10T03:49:34Z |
| format | Article |
| id | doaj.art-b0bb437a497e40dda07c36c18df2c97d |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T03:49:34Z |
| publishDate | 2022-05-01 |
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| series | Genes |
| spelling | doaj.art-b0bb437a497e40dda07c36c18df2c97d2023-11-23T11:10:29ZengMDPI AGGenes2073-44252022-05-0113585110.3390/genes13050851A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell CarcinomaZilong Bian0Rong Fan1Lingmin Xie2Department of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Big Data in Health Science, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, ChinaDepartment of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, ChinaClear 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 <i>CDKN2A</i>, <i>DLAT</i>, <i>DLD</i>, <i>FDX1</i>, <i>GLS</i>, <i>PDHA1</i> and <i>PDHB</i> exhibited differential expression between ccRCC and normal tissues (|log<sub>2</sub>(fold change)| > 2/3 and <i>p</i> < 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 (<i>HR</i> = 2.72 (2.01–3.68), log-rank <i>p</i> = 1.76 × 10<sup>−7</sup>). Patients with a higher risk had a significantly shorter PFS (<i>HR</i> = 2.83 (2.08–3.85), log-rank <i>p</i> = 3.66 × 10<sup>−7</sup>). Two independent validation datasets (GSE40435 (<i>N</i> = 101), GSE53757 (<i>N</i> = 72)) were collected for meta-analysis, suggesting that CDKN2A (log<sub>2</sub>(fold change) = 1.46, 95%CI: 1.75–2.35) showed significantly higher expression in ccRCC tissues while DLAT (log<sub>2</sub>(fold change) = −0.54, 95%CI: −0.93–−0.15) and FDX1 (log<sub>2</sub>(fold change) = −1.01, 95%CI: −1.61–−0.42) were lowly expressed. The expression of <i>CDKN2A</i> and <i>FDX1</i> in ccRCC was also significantly associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: <i>r</i> = 0.24, <i>p</i> = 2.14 × 10<sup>−8</sup>; FDX1: <i>r</i> = −0.17, <i>p</i> = 1.37 × 10<sup>−4</sup>). 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.https://www.mdpi.com/2073-4425/13/5/851cuproptosisccRCCoverall survivalprogression-free survivalcell death |
| spellingShingle | Zilong Bian Rong Fan Lingmin Xie A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma Genes cuproptosis ccRCC overall survival progression-free survival cell death |
| title | A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma |
| title_full | A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma |
| title_fullStr | A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma |
| title_short | A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma |
| title_sort | novel cuproptosis related prognostic gene signature and validation of differential expression in clear cell renal cell carcinoma |
| topic | cuproptosis ccRCC overall survival progression-free survival cell death |
| url | https://www.mdpi.com/2073-4425/13/5/851 |
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