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Prognostic Score-based Clinical Factors and Metabolism-related Biomarkers for Predicting the Progression of Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is a common malignant tumor representing more than 90% of primary liver cancer. This study aimed to identify metabolism-related biomarkers with prognostic value by developing the novel prognostic score (PS) model. Transcriptomic profiles derived from TCGA and EBIArray databases were analyzed to identify differentially expressed genes (DEGs) in HCC tumor samples compared with normal samples. The overlapped genes between DEGs and metabolism-related genes (crucial genes) were screened and functionally analyzed. A novel PS model was constructed to identify optimal signature genes. Cox regression analysis was performed to identify independent clinical factors related to prognosis. Nomogram model was constructed to estimate the predictability of clinical factors. Finally, protein expression of crucial genes was explored in different cancer tissues and cell types from the Human Protein Atlas (HPA). We screened a total of 305 overlapped genes (differentially expressed metabolism-related genes). These genes were mainly involved in "oxidation reduction," "steroid hormone biosynthesis," "fatty acid metabolic process," and "linoleic acid metabolism." Furthermore, we screened ten optimal DEGs (CYP2C9, CYP3A4, and TKT, among others) by using the PS model. Two clinical factors of pathologic stage (P < .001, HR: 1.512 [1.219-1.875]) and PS status (P <.001, HR: 2.259 [1.522-3.354]) were independent prognostic predictors by cox regression analysis. Nomogram model showed a high predicted probability of overall survival time, and the AUC value was 0.837. The expression status of 7 proteins was frequently altered in normal or differential tumor tissues, such as liver cancer and stomach cancer samples.We have identified several metabolism-related biomarkers for prognosis prediction of HCC based on the PS model. Two clinical factors were independent prognostic predictors of pathologic stage and PS status (high/low risk). The prognosis prediction model described in this study is a useful and stable method for novel biomarker identification.

SUBMITTER: Yan J

PROVIDER: S-EPMC7518001 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Prognostic Score-based Clinical Factors and Metabolism-related Biomarkers for Predicting the Progression of Hepatocellular Carcinoma.

Yan Jia J Shu Ming M Li Xiang X Yu Hua H Chen Shuhuai S Xie Shujie S

Evolutionary bioinformatics online 20200922

Hepatocellular carcinoma (HCC) is a common malignant tumor representing more than 90% of primary liver cancer. This study aimed to identify metabolism-related biomarkers with prognostic value by developing the novel prognostic score (PS) model. Transcriptomic profiles derived from TCGA and EBIArray databases were analyzed to identify differentially expressed genes (DEGs) in HCC tumor samples compared with normal samples. The overlapped genes between DEGs and metabolism-related genes (crucial gen ...[more]

PMID: 33013158

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the main causes of cancer-associated deaths globally, accounts for 90% of primary liver cancers. However, further studies are needed to confirm the metabolism-related gene signature related to the prognosis of patients with HCC.MethodsUsing the "limma" R package and univariate Cox analysis, combined with LASSO regression analysis, a metabolism-related gene signature was established. The relationship between the gene signature and overall survival (OS) of HCC patients was analyzed. RT-qPCR was used to evaluate the expression of metabolism-related genes in clinical samples. GSEA and ssGSEA algorithms were used to evaluate differences in metabolism and immune status, respectively. Simultaneously, data downloaded from ICGC were used as an external verification set.ResultsFrom a total of 1,382 metabolism-related genes, a novel six-gene signature (G6PD, AKR1B15, HMMR, CSPG5, ELOVL3, FABP6) was constructed based on data from TCGA. Patients were divided into two risk groups based on risk scores calculated for these six genes. Survival analysis showed a significant correlation between high-risk patients and poor prognosis. ROC analysis demonstrated that the gene signature had good predictive capability, and the mRNA expression levels of the six genes were upregulated in HCC tissues than those in adjacent normal liver tissues. Independent prognosis analysis confirmed that the risk score and tumor grade were independent risk factors for HCC. Furthermore, a nomogram of the risk score combined with tumor stage was constructed. The calibration graph results demonstrated that the OS probability predicted by the nomogram had almost no deviation from the actual OS probability, especially for 3-year OS. Both the C-index and DCA curve indicated that the nomogram provides higher reliability than the tumor stage and risk scores. Moreover, the metabolic and immune infiltration statuses of the two risk groups were significantly different. In the high-risk group, the expression levels of immune checkpoints, TGF-β, and C-ECM genes, whose functions are related to immune escape and immunotherapy failure, were also upregulated.ConclusionsIn summary, we developed a novel metabolism-related gene signature to provide more powerful prognostic evaluation information with potential ability to predict the immunotherapy efficiency and guide early treatment for HCC.

Project description:BackgroundExosomes are involved in cell-to-cell communication, neovascularization, cancer metastasis, and drug resistance, which all play an important role in the occurrence and progression of hepatocellular carcinoma (HCC). Because there are few mechanistic studies about the function of exosomes in HCC, the goals of this study were to identify exosome-related genes in HCC, to establish a reliable prognostic model for HCC, and to explore underlying mechanisms.MethodsThe exoRBase and The Cancer Genome Atlas (TCGA) databases were used to analyze differentially expressed genes (DEGs). Cox regression and least absolute shrinkage and selection operator analyses were used to identify DEGs closely related to the overall survival of patients with HCC. An exosome-related prognostic model was then constructed in TCGA and validated in the International Cancer Genome Consortium database. A nomogram was developed to predict survival. CIBERSORT was used to estimate the abundance of different types of immune cells. Immunotherapy-related DEGs were used to predict the effect of immunotherapy.ResultsForty-eight exosome-related DEGs were obtained; of them, five [exportin 1 (XPO1), lysosomal thiol reductase (IFI30), F-box protein 16 (FBXO16), calmodulin 1 (CALM1), MORC family CW-type zinc finger 3 (MORC3)] were selected to construct a predictive model. Patients with HCC were then divided into low- and high-risk groups using the best cut-off value, as determined by the X-tile software. Prognosis was significantly poorer in the high-risk than in the low-risk group (P=0.009; hazard ratio =2.65). Features related to exosomes were found to positively regulate immune response. Further analysis showed a higher risk score was associated with higher expression of immune checkpoint molecules, including programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell Ig and ITIM domain (TIGIT), and indoleamine-2,3-dioxygenase 1 (IDO1).ConclusionsThis study has identified a novel signature based on exosome-related genes that has potential as a prognostic biomarker for HCC. Our research provides an immunological perspective for the development of precision treatment for HCC.

Dataset Information

Prognostic Score-based Clinical Factors and Metabolism-related Biomarkers for Predicting the Progression of Hepatocellular Carcinoma.

Publications

Prognostic Score-based Clinical Factors and Metabolism-related Biomarkers for Predicting the Progression of Hepatocellular Carcinoma.

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