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Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC.

ABSTRACT: Background: Hepatocellular carcinoma (HCC) is the world's second most deadly cancer, and metabolic reprogramming is its distinguishing feature. Among metabolite profiling, variation in amino acid metabolism supports tumor proliferation and metastasis to the most extent, yet a systematic study on the role of amino acid metabolism-related genes in HCC is still lacking. An effective amino acid metabolism-related prediction signature is urgently needed to assess the prognosis of HCC patients for individualized treatment. Materials and Methods: RNA-seq data of HCC from the TCGA-LIHC and GSE14520 (GPL3921) datasets were defined as the training set and validation set, respectively. Amino acid metabolic genes were extracted from the Molecular Signature Database. Univariate Cox and LASSO regression analyses were performed to build a predictive risk signature. K-M curves, ROC curves, and univariate and multivariate Cox regression were conducted to evaluate the predictive value of this risk signature. Functional enrichment was analyzed by GSEA and CIBERSORTx software. Results: A nine-gene amino acid metabolism-related risk signature including B3GAT3, B4GALT2, CYB5R3, GNPDA1, GOT2, HEXB, HMGCS2, PLOD2, and SEPHS1 was constructed to predict the overall survival (OS) of HCC patients. Patients were separated into high-risk and low-risk groups based on risk scores and low-risk patients had lower risk scores and longer survival time. Univariate and multivariate Cox regression verified that this signature was an independent risk factor for HCC. ROC curves showed that this risk signature can effectively predict the 1-, 2-, 3- and 5-year survival times of patients with HCC. Additionally, prognostic nomograms were established based on the training set and validation set. These genes were closely correlated with the immune regulation. Conclusion: Our study identified a nine-gene amino acid metabolism-related risk signature and built predictive nomograms for OS in HCC. These findings will help us to personalize the treatment of liver cancer patients.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC8452960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRenal cancer is one of the most lethal cancers because of its atypical symptoms and metastatic potential. The metabolism of amino acids and their derivatives is essential for cancer cell survival and proliferation. Thus, the construction of the amino acid metabolism-related risk signature might enhance the accuracy of the prognostic model and shed light on the treatments of renal cancers.MethodsRNA expression and clinical data were downloaded from Santa Cruz (UCSC) Xena, GEO, and ArrayExpress databases. The "DESeq2" package identified the differentially expressed genes. Univariate COX analysis selected prognostic genes related to the metabolism of amino acids. Patients were divided into two clusters using the "ConsensusClusterPlus" package, and the CIBERSORT, ESTIMATE methods were explored to assess the immune infiltrations. The LASSO regression analysis constructed a risk model which was evaluated the prediction accuracy in two independent cohorts. The genomic alterations and drug sensitivity of 18-LASSO-genes were assessed. The differentially expressed genes between two clusters were used to perform functional enrichment analysis and weighted gene co-expression network analysis (WGCNA). Furthermore, external validation of TMEM72 expression was conducted in the FUSCC cohort containing 33 ccRCC patients.ResultsThe amino acid metabolism-related genes had significant correlations with prognosis. The patients in Cluster A demonstrated better survival, lower Treg cell proportion, higher ESTIMATE scores, and higher cuproptosis-related gene expressions. Amino acid metabolism-related genes with prognostic values were used to construct a risk model and patients in the low risk group were associated with improved outcomes. The Area Under Curve of the risk model was 0.801, 0.777, and 0.767 at the first, second, and third year respectively. The external validation cohort confirmed the stable prognostic value of the risk model. WGCNA identified four gene modules correlated with immune cell infiltrations and cuproptosis. We found that TMEM72 was downregulated in tumors by using TCGA, GEO datasets (p<0.001) and the FUSCC cohort (p=0.002).ConclusionOur study firstly constructed an 18 amino acid metabolism related signature to predict the prognosis in clear cell renal cell carcinoma. We also identified four potential gene modules potentially correlated with cuproptosis and identified TMEM72 downregulation in ccRCC which deserved further studies.

Project description:Energy metabolic processes play important roles for tumor malignancy, indicating that related protein-coding genes and regulatory upstream genes (such as long noncoding RNAs (lncRNAs)) may represent potential biomarkers for prognostic prediction. This study will develop a new energy metabolism-related lncRNA-mRNA prognostic signature for lower-grade glioma (LGG) patients. A GSE4290 dataset obtained from Gene Expression Omnibus was used for screening the differentially expressed genes (DEGs) and lncRNAs (DELs). The Cancer Genome Atlas (TCGA) dataset was used as the prognosis training set, while the Chinese Glioma Genome Atlas (CGGA) was for the validation set. Energy metabolism-related genes were collected from the Molecular Signatures Database (MsigDB), and a coexpression network was established between energy metabolism-related DEGs and DELs to identify energy metabolism-related DELs. Least absolute shrinkage and selection operator (LASSO) analysis was performed to filter the prognostic signature which underwent survival analysis and nomogram construction. A total of 1613 DEGs and 37 DELs were identified between LGG and normal brain tissues. One hundred and ten DEGs were overlapped with energy metabolism-related genes. Twenty-seven DELs could coexpress with 67 metabolism-related DEGs. LASSO regression analysis showed that 9 genes in the coexpression network were the optimal signature and used to construct the risk score. Kaplan-Meier curve analysis showed that patients with a high risk score had significantly worse OS than those with a low risk score (TCGA: HR = 3.192, 95%CI = 2.182-4.670; CGGA: HR = 1.922, 95%CI = 1.431-2.583). The predictive accuracy of the risk score was also high according to the AUC of the ROC curve (TCGA: 0.827; CGGA: 0.806). Multivariate Cox regression analyses revealed age, IDH1 mutation, and risk score as independent prognostic factors, and thus, a prognostic nomogram was established based on these three variables. The excellent prognostic performance of the nomogram was confirmed by calibration and discrimination analyses. In conclusion, our findings provided a new biomarker for the stratification of LGG patients with poor prognosis.

Project description:Background: Amino acid metabolism (AAM) deregulation, an emerging metabolic hallmark of malignancy, plays an essential role in tumour proliferation, invasion, and metastasis. However, the expression of AAM-related genes and their correlation with prognosis in clear cell renal cell carcinoma (ccRCC) remain elusive. This study aims to develop a novel consensus signature based on the AAM-related genes. Methods: The RNA-seq expression data and clinical information for ccRCC were downloaded from the TCGA (KIRC as training dataset) and ArrayExpress (E-MTAB-1980 as validation dataset) databases. The AAM-related differentially expressed genes were screened via the "limma" package in TCGA cohorts for further analysis. The machine learning algorithms (Lasso and stepwise Cox (direction = both)) were then utilised to establish a novel consensus signature in TCGA cohorts, which was validated by the E-MTAB-1980 cohorts. The optimal cutoff value determined by the "survminer" package was used to categorise patients into two risk categories. The Kaplan-Meier curve, the receiver operating characteristic (ROC) curve, and multivariate Cox regression were utilised to evaluate the prognostic value. The nomogram based on the gene signature was constructed, and its performance was analysed using ROC and calibration curves. Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis were conducted on its potential mechanisms. The relationship between the gene signature and key immune checkpoint, N6-methyladenosine (m6A)-related genes, and sensitivity to chemotherapy was assessed. Results: A novel consensus AMM-related gene signature consisting of IYD, NNMT, ACADSB, GLDC, and PSAT1 is developed to predict prognosis in TCGA cohorts. Kaplan-Meier survival shows that overall survival in the high-risk group was more dismal than in the low-risk group in the TCGA cohort, validated by the E-MTAB-1980 cohort. Multivariate regression analysis also demonstrates that the gene signature is an independent predictor of ccRCC. Immune infiltration analysis highlighted that the high-risk group indicates an immunosuppressive microenvironment. It is also closely related to the level of key immune checkpoints, m6A modification, and sensitivity to chemotherapy drugs. Conclusion: In this study, a novel consensus AAM-related gene signature is developed and validated as an independent predictor to robustly predict the overall survival from ccRCC, which would further improve the clinical outcomes.

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Identification and Validation of a Nine-Gene Amino Acid Metabolism-Related Risk Signature in HCC.

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