Dataset Information

Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

ABSTRACT: BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performed for mechanistic analysis. xCell deconvolution was performed for tumor microenvironment analysis. RESULTS In the TCGA-ACC cohort, WGCNA identified a prognostic module of 5408 genes. Differential expression analysis identified 1969 genes that differed in expression level between long-term and short-term survivors. Univariate Cox regression model analysis identified 8393 genes with prognostic value. The intersection of these gene sets included 820 prognostic genes. Similar protocols were performed for the GSE76021 dataset, and 5 candidate genes were identified. Further intersection of these genes finally identified NDRG4 and CKS2 as key prognostic genes. Multivariate Cox regression model analysis validated the prognostic value of NDRG4 (HR=0.61, 95% CI 0.46-0.80) and CKS2 (HR=2.52, 95% CI 1.38-4.60). Moreover, NDRG4 and CKS2 expression predicted survival in patients treated with mitotane (P<0.001). Further mechanism exploration found an association between CKS2 and DNA mismatch repair pathways. Moreover, NDRG4 positively correlated with CD8? T cell infiltration, while CKS2 negatively correlated with it. CONCLUSIONS We identified NDRG4 and CKS2 expression as key prognostic genes in ACC, which may help in risk stratification of ACC. Moreover, a close relationship was found between CKS2 and mismatch repair pathways. Moreover, immune cell infiltration differed according to NDRG4 and CKS2 expression.

SUBMITTER: Yang Z

PROVIDER: S-EPMC7941762 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

Yang Zhengqing Z Cheng Hui H Zhang Yazhou Y Zhou Yan Y

Medical science monitor : international medical journal of experimental and clinical research 20210305

BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performe ...[more]

PMID: 33667214

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Project description:Gliomas account for the highest cases of primary brain malignancies. Whereas previous studies have demonstrated the roles of CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) in various cancer types, its functions in lower grade gliomas (LGGs) remain elusive. This study aimed to profile the expression and functions of CKS2 in LGG. Multiple online databases such as The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), Gene Expression Profiling Interactive Analysis 2nd edition (GEPIA2), Tumor Immune Estimation Resource 2nd edition (TIMER2.0) as well as Gene Expression Omnibus (GEO) were used in this study. Immunohistochemistry (IHC) was performed to evaluate CKS2 protein expression. Our data demonstrated upregulation of CKS2 in LGG tissues at both mRNA and protein level, especially in grade III gliomas. Similarly, there was increased expression of CKS2 in isocitrate dehydrogenase 1 (IDH1) wildtype gliomas. In addition, increased DNA copy number and DNA hypomethylation might be associated with the upregulation of the CKS2 in LGG. Using the Kaplan-Meier survival analysis and the Cox regression analysis, CKS2 was shown to be independently associated with poor prognosis of LGG patients. Receiver operating characteristic (ROC) analysis revealed that CKS2 could effectively predict the 1-, 3- and 5-year survival rates of LGG patients. Enrichment analyses revealed that CKS2 was mainly involved in the regulation of the cell cycle in LGG. Taken together, our study demonstrated that CKS2 might be a candidate prognostic biomarker for LGG and could predict the survival rates of LGG patients.Abbreviations: LGG: lower grade glioma; CKS2: CDC28 protein kinase regulatory subunit 2; TCGA: The Cancer Genome Atlas; CGGA: the Chinese Glioma Genome Atlas; GEO: Gene Expression Omnibus; GEPIA: Gene Expression Profiling Interactive Analysis; TIMER: Tumor Immune Estimation Resource; IHC: immunohistochemistry; qRT-PCR: quantitative real-time polymerase chain reaction; PBS: phosphate buffered saline; DAB: diaminobenzidine tetrachloride; OS: overall survival; CAN: copy number alteration; IDH: Isocitrate dehydrogenase; GSEA: Gene Set Enrichment Analysis; DEG: differentially expressed gene; KEGG: Kyoto encyclopedia of genes and genomes; GO: Gene ontology; BP: biological process; CC: cellular component; MF: molecular function; NES: normalized enrichment score; NOM: nominal; FDR: false discovery rate.

Project description:ObjectivesThis study aimed to systematically elucidate the prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) expression in various cancers and its correlation with their clinicopathological characteristics.DesignIn this meta-analysis and bioinformatic analysis, articles were identified through searches of multiple databases and meta-analysed according to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. Data from The Cancer Genome Atlas were examined using UCSC Xena tools to further confirm the prognostic effect of CKS2.Data sourcesThe PubMed, Embase, Web of Science and Cochrane Library databases were searched for articles published from their inception to 1 January 2023, using a combination of subject terms and free words, including 'CKS2', 'cancer', 'tumor', 'neoplasm', 'carcinoma', 'malignancy' and 'prognosis'.Eligibility criteriaThe analysis included cohort or case-control studies, reported in English, with malignancy diagnoses confirmed by pathological methods, available HRs and 95% CIs for overall survival (OS) or extractable Kaplan-Meier curves, and a sample size of ≥20 patients. Reviews, commentaries, letters, conference reports, case reports, in vitro and animal studies, studies of CKS2 gene variants, studies with sample cases from public databases and studies with unavailable survival or duplicated data were excluded.Data extraction and synthesisTwo researchers independently screened the articles, extracted the data and evaluated the quality of included studies using the Newcastle-Ottawa Scale. Meta-analysis and bioinformatic analyses were performed using the STATA and R software, respectively.ResultsThe analysis included 13 retrospective studies encompassing 1348 cases across 10 cancer types. Nine studies involving 1124 patients examined the correlation between CKS2 expression levels and OS. A fixed-effects model analysis revealed a significant association between high CKS2 expression and reduced OS (HR=2.27, 95% CI=1.87 to 2.77, p<0.001). Furthermore, high CKS2 expression was significantly associated with advanced tumour stage (relative risk (RR) = 1.82, 95% CI=1.57 to 2.11, p<0.001), lymph node metastasis (RR=1.68, 95% CI=1.38 to 2.04, p<0.001), larger tumour size (RR=1.60, 95% CI=1.27 to 2.03, p<0.001) and lower differentiation grade (RR=1.57, 95% CI=1.29 to 1.90, p<0.001). CKS2 expression levels were not significantly correlated with patients' age (RR=1.11, 95% CI=0.99 to 1.26, p=0.071) or sex (RR=0.98, 95% CI=0.90 to 1.07, p=0.653). An assessment of the articles showed no significant publication bias, confirming the robustness of these findings. The bioinformatic analysis further confirmed CKS2 upregulation in the examined cancer types and its association with poor OS in glioma (HR=1.97, 95% CI=1.78 to 2.18, p=3.70×10-42), liver hepatocellular carcinoma (HR=1.56, 95% CI=1.31 to 1.86, p=3.50×10-7) and lung adenocarcinoma (HR=1.27, 95% CI=1.10 to 1.48, p=1.70×10-3).ConclusionsElevated CKS2 expression is associated with poor prognosis in a subset of malignant tumours, highlighting its potential as a prognostic marker.Prospero registration numberCRD42023394038.

Project description:Background:Lung adenocarcinoma (ACA) is the most common subtype of non-small-cell lung cancer. About 70%-80% patients are diagnosed at an advanced stage; therefore, the survival rate is poor. It is urgent to discover accurate markers that can differentiate the late stages of lung ACA from the early stages. With the development of biochips, researchers are able to efficiently screen large amounts of biological analytes for multiple purposes. Methods:Our team downloaded GSE75037 and GSE32863 from the Gene Expression Omnibus (GEO) database. Next, we utilized GEO's online tool, GEO2R, to analyze the differentially expressed genes (DEGs) between stage I and stage II-IV lung ACA. The using the Cytoscape software was used to analyze the DEGs and the protein-protein interaction (PPI) network was further constructed. The function of the DEGs were further analyzed by cBioPortal and Gene Expression Profiling Interactive Analysis (GEPIA) online tools. We validated these results in 72 pairs human samples. Results:We identified 109 co-DEGs, most of which were involved in either proliferation, S phase of mitotic cell cycle, regulation of exit from mitosis, DNA replication initiation, DNA replication, and chromosome segregation. Utilizing cBioPortal and University of California Santa Cruz databases, we further confirmed 35 hub genes. Two of these genes, encoding CDC28 protein kinase regulatory subunit 2 (CKS2) and RecQ-mediated genome instability 2 (RMI2), were upregulated in lung ACA compared with adjacent normal tissues. The Kaplan-Meier curves revealed upregulation of CKS2 and RMI2 are associated with worse survival. Using CMap analysis, we discovered 10 small molecular compounds that reversed the altered DEGs, the top five are phenoxybenzamine, adiphenine, resveratrol, and trifluoperazine. We also evaluated 72 pairs resected samples, results revealed that upregulation of CKS2 and RMI2 in lung ACA were associated with larger tumor size. Our results allow the deeper recognizing of the mechanisms of the progression of lung ACA, and may indicate potential therapeutic strategies for the therapy of lung ACA.

Dataset Information

Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

Publications

Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

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