Dataset Information

Cuproptosis-Related Genes Are Associated with Cell Cycle and Serve as the Prognostic Signature for Clear Cell Renal Cell Carcinoma.

ABSTRACT: Cuproptosis is a newly discovered type of cell death. The role and potential mechanism of Cuproptosis-related genes (CRGs) in the prognosis of cancer patients are not fully understood. In this study, we included two cohorts of clear cell renal cell carcinoma patients, TCGA and E-MTAB-1980. The TCGA cohort is used as a training set to construct a CRG signature using the LASSO-cox regression analysis, and E-MTAB-1980 is used as a cohort for verification. A total of eight genes (FDX1, LIAS, LIPT1, DLAT, PDHA1, MTF1, GLS, CDKN2A) were screened to construct a prognostic model in the TCGA cohort. There is a significant difference in OS (p < 0.0001) between the high and low cuproptosis score group, and a similar difference is also observed in the OS (p = 0.0054) of the E-MTAB-1980 cohort. The area under the ROC curves (AUC) were 0.87, 0.82, and 0.78 at 1, 3, and 5 years in the TCGA cohort, respectively. Finally, gene set enrichment analysis revealed that CRGs were associated with cell cycle and mitotic signaling pathways.

SUBMITTER: Guo T

PROVIDER: S-EPMC9782129 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cuproptosis-Related Genes Are Associated with Cell Cycle and Serve as the Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Guo Tuanjie T Zhang Jian J Yuan Zhihao Z Tang Heting H Wang Tao T Wang Xiang X Chen Siteng S

Journal of clinical medicine 20221218 24

Cuproptosis is a newly discovered type of cell death. The role and potential mechanism of Cuproptosis-related genes (CRGs) in the prognosis of cancer patients are not fully understood. In this study, we included two cohorts of clear cell renal cell carcinoma patients, TCGA and E-MTAB-1980. The TCGA cohort is used as a training set to construct a CRG signature using the LASSO-cox regression analysis, and E-MTAB-1980 is used as a cohort for verification. A total of eight genes (FDX1, LIAS, LIPT1, ...[more]

PMID: 36556123

Similar Datasets

Project 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 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.

Project description:Objective Cuproptosis, a nascent and unique pattern of cell death, is poised to spark a new rush of biological research. Yet, the subsumed mechanism of cuproptosis in carcinoma is not wholly clarified. The exclusive aim of this work is to define a novel classification algorithm and risk-prognosis scoring framework based on the expression modalities of cuproptosis genes to monitor clear cell renal cell carcinoma (ccRCC) patients’ prognosis and immunotherapeutic response. Methods We pooled ccRCC data from three large-scale databases as the training subset and gathered a panel of clinical queues, termed the Taizhou cohort, which served as the validation setup. Wilcox test was conducted for comparison of expression variation, while the cox analysis and KM curves were utilized to visualize prognosis. Unsupervised clustering analysis was used to identify cuproptosis phenotypes in ccRCC. Concurrently, LASSO regression-based computational scoring model. A step further, gene set enrichment analysis (GSEA) was performed to check potential biological processes and the “CIBERSORT” R package was used to estimate the proportion of immune cells. To last, immunohistochemistry and qRT-PCR were carried out for the assay of critical genes for cuproptosis. Results Here, we glimpse the prognostic power of cuproptosis genes in pan-cancer by investigating 33 cancers with multi-omics data to map their genetic heterogeneity landscape. In parallel, we devoted extra attention to their strategic potential role in ccRCC, identifying two phenotypes of cuproptosis with different immune microenvironmental characteristics by pooling ccRCC data from three large-scale databases. Additionally, we compiled a cuproptosis scoring system for clinicians to determine the prognosis, immunotherapy response, and chemosensitivity of ccRCC patients. Notably, we assembled a clinical cohort sample to validate the pivotal gene for cuproptosis, FDX1, to supply more clues to translate the biological significance of cuproptosis in ccRCC. Conclusion In all, our investigations highlight that cuproptosis is involved in various components of ccRCC and assists in the formation of the tumor immune microenvironment. These results provide partial insights to further comprehend the molecular mechanisms of cuproptosis in ccRCC and could be helpful for the development of personalized therapeutic strategies targeting copper or cuproptosis.

Project description:Background: Cuproptosis has been found as a novel cell death mode significantly associated with mitochondrial metabolism, which may be significantly associated with the occurrence and growth of tumors. LncRNAs take on critical significance in regulating the development of kidney renal clear cell carcinoma (KIRC), whereas the correlation between cuproptosis-related LncRNAs (CRLs) and KIRC is not clear at present. Therefore, this study built a prognosis signature based on CRLs, which can achieve accurate prediction of the outcome of KIRC patients. Methods: The TCGA database provided the expression profile information and relevant clinical information of KIRC patients. Univariate Cox, Lasso, and multivariate Cox were employed for building a risk signature based on CRLs. Kaplan-Meier (K-M) survival analysis and time-dependent receiver operating characteristic (ROC) curve were employed for the verification and evaluation of the reliability and accuracy of risk signature. Then, qRT-PCR analysis of risk LncRNAs was conducted. Finally, the possible effect of the developed risk signature on the microenvironment for tumor immunization was speculated in accordance with ssGSEA and ESTIMATE algorithms. Results: A prognosis signature composed of APCDD1L-DT, MINCR, AL161782.1, and AC026401.3 was built based on CRLs. As revealed by the results of the K-M survival study, the OS rate and progression-free survival rate of highrisk KIRC patients were lower than those of lowrisk KIRC patients, and the areas under ROC curves of 1, 3, and 5 years were 0.828, 0.780, and 0.794, separately. The results of the immune analysis showed that there were significant differences in the status of immunization and the microenvironment of tumor between groups at low-risk and at high-risk. The qRT-PCR results showed that the relative expression level of MINCR and APCDD1L-DT were higher in 786-O and 769-P tumor cells than in HK-2 cells, which were normal renal tubular epithelial cells. Conclusion: The developed risk signature takes on critical significance in the prediction of the prognosis of patients with KIRC, and it can bring a novel direction for immunotherapy and clinical drug treatment of KIRC. In addition, 4 identified risk LncRNAs (especially APCDD1L-DT and MINCR) can be novel targets for immunotherapy of KIRC patients.

Dataset Information

Cuproptosis-Related Genes Are Associated with Cell Cycle and Serve as the Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Publications

Cuproptosis-Related Genes Are Associated with Cell Cycle and Serve as the Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets