Dataset Information

The Prognostic Model Based on Tumor Cell Evolution Trajectory Reveals a Different Risk Group of Hepatocellular Carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and heterogeneity of HCC is the major barrier in improving patient outcome. To stratify HCC patients with different degrees of malignancy and provide precise treatment strategies, we reconstructed the tumor evolution trajectory with the help of scRNA-seq data and established a 30-gene prognostic model to identify the malignant state in HCC. Patients were divided into high-risk and low-risk groups. C-index and receiver operating characteristic (ROC) curve confirmed the excellent predictive value of this model. Downstream analysis revealed the underlying molecular and functional characteristics of this model, including significantly higher genomic instability and stronger proliferation/progression potential in the high-risk group. In summary, we established a novel prognostic model to overcome the barriers caused by HCC heterogeneity and provide the possibility of better clinical management for HCC patients to improve their survival outcomes.

SUBMITTER: Wang H

PROVIDER: S-EPMC8511531 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The Prognostic Model Based on Tumor Cell Evolution Trajectory Reveals a Different Risk Group of Hepatocellular Carcinoma.

Wang Haoren H Yu Shizhe S Cai Qiang Q Ma Duo D Yang Lingpeng L Zhao Jian J Jiang Long L Zhang Xinyi X Yu Zhiyong Z

Frontiers in cell and developmental biology 20210929

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and heterogeneity of HCC is the major barrier in improving patient outcome. To stratify HCC patients with different degrees of malignancy and provide precise treatment strategies, we reconstructed the tumor evolution trajectory with the help of scRNA-seq data and established a 30-gene prognostic model to identify the malignant state in HCC. Patients were divided into high-risk and low-risk groups. C-in ...[more]

PMID: 34660596

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Project description:BackgroundVarious studies highlighted that immune cell-mediated inflammatory processes play crucial roles in the progression and treatment of hepatocellular carcinoma (HCC). However, the immune microenvironment of HCC is still poorly characterized. Exploring the role of immune-related genes (IRGs) and describing the immune landscape in HCC would provide insights into tumor-immune co-evolution along HCC progression.MethodsWe integrated the datasets with complete prognostic information from the Cancer Genome Atlas (TCGA) database and GEO DataSets (GSE14520, GSE76427, and GSE54236) to construct a novel immune landscape based on the Cibersort algorithm and reveal the prognostic signature in HCC patients.ResultsTo describe the tumor microenvironment (TME) in HCC, immune infiltration patterns were defined using the CIBERSORT method, and a prognostic signature contains 5 types of immune cells, including 3 high-risk immune cells (T.cells. CD4. memory. resting, Macrophages.M0, Macrophages.M2) and 2 low-risk immune cells (Plasma. cells, T.cells.CD8), were finally constructed. A novel prognostic index, based on prognostic immune risk score (pIRG), was developed using the univariate Cox regression analyses and LASSO Cox regression algorithm. Furthermore, the ROC curve and KM curve showed that the TME signatures had a stable value in predicting the prognosis of HCC patients in the internal training cohort, internal validation, and external validation cohort. Differential genes analysis and qPCR experiment showed that the expression levels of AKR1B10, LAPTM4B, MMP9, and SPP1 were significantly increased in high-risk patients, while the expression of CD5L was lower. Further analysis found that AKR1B10 and MMP9 were associated with higher M0 macrophage infiltration, while CD5L was associated with higher plasma cell infiltration.ConclusionsTaken together, we performed a comprehensive evaluation of the immune landscape of HCC and constructed a novel and robust prognostic prediction model. AKR1B10, LAPTM4B, MMP9, SPP1, and CD5L were involved in important processes in the HCC tumor microenvironment and were expected to become HCC prediction markers and potential targets of treatment.

Project description:BackgroundHepatocellular carcinoma (HCC) was the sixth common malignancies characteristic with highly aggressive in the world. It was well established that tumor mutation burden (TMB) act as indicator of immunotherapeutic responsiveness in various tumors. However, the role of TMB in tumor immune microenvironment (TIME) is still obscure.MethodThe mutation data was analyzed by employing "maftools" package. Weighted gene co-expression network analysis (WGCNA) was implemented to determine candidate module and significant genes correlated with TMB value. Differential analysis was performed between different level of TMB subgroups employing R package "limma". Gene ontology (GO) enrichment analysis was implemented with "clusterProfiler", "enrichplot" and "ggplot2" packages. Then risk score signature was developed by systematical bioinformatics analyses. K-M survival curves and receiver operating characteristic (ROC) plot were further analyzed for prognostic validity. To depict comprehensive context of TIME, XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT, and CIBERSORT-ABS algorithm were employed. Additionally, the potential role of risk score on immune checkpoint blockade (ICB) immunotherapy was further explored. The quantitative real-time polymerase chain reaction was performed to detect expression of HTRA3.ResultsTMB value was positively correlated with older age, male gender and early T status. A total of 75 intersection genes between TMB-related genes and differentially expressed genes (DEGs) were screened and enriched in extracellular matrix-relevant pathways. Risk score based on three hub genes significantly affected overall survival (OS) time, infiltration of immune cells, and ICB-related hub targets. The prognostic performance of risks score was validated in the external testing group. Risk-clinical nomogram was constructed for clinical application. HTRA3 was demonstrated to be a prognostic factor in HCC in further exploration. Finally, mutation of TP53 was correlated with risk score and do not interfere with risk score-based prognostic prediction.ConclusionCollectively, a comprehensive analysis of TMB might provide novel insights into mutation-driven mechanism of tumorigenesis further contribute to tailored immunotherapy and prognosis prediction of HCC.

Dataset Information

The Prognostic Model Based on Tumor Cell Evolution Trajectory Reveals a Different Risk Group of Hepatocellular Carcinoma.

Publications

The Prognostic Model Based on Tumor Cell Evolution Trajectory Reveals a Different Risk Group of Hepatocellular Carcinoma.

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