Dataset Information

Comprehensive Analysis of Histone Modifications in Hepatocellular Carcinoma Reveals Different Subtypes and Key Prognostic Models.

ABSTRACT: Histone modification, an important epigenetic mechanism, is related to the carcinogenesis of hepatocellular carcinoma (HCC). In three datasets, we screened 88 epigenetic-dysregulated PCGs (epi-PCGs) , which were significantly associated with HCC survival and could cluster HCC into three molecular subtypes. These subtypes were associated with prognosis, immunomodulatory alterations, and response to different treatment strategies. Based on 88 epi-PCGs in the TCGA training set, a risk prediction model composed of 4 epi-PCGs was established. The model was closely related to the clinicopathological features and showed a strong predictive ability in different clinical subgroups. In addition, the risk prediction model was an independent prognostic factor for patients with HCC. The significance of epi-PCGs in HCC is revealed by our data analysis.

SUBMITTER: Li H

PROVIDER: S-EPMC9359864 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Comprehensive Analysis of Histone Modifications in Hepatocellular Carcinoma Reveals Different Subtypes and Key Prognostic Models.

Li Huikai H Mu Han H Xiao Yajie Y Zhao Zhikun Z Cui Xiaoli X Wu Dongfang D

Journal of oncology 20220801

Histone modification, an important epigenetic mechanism, is related to the carcinogenesis of hepatocellular carcinoma (HCC). In three datasets, we screened 88 epigenetic-dysregulated PCGs (epi-PCGs) , which were significantly associated with HCC survival and could cluster HCC into three molecular subtypes. These subtypes were associated with prognosis, immunomodulatory alterations, and response to different treatment strategies. Based on 88 epi-PCGs in the TCGA training set, a risk prediction mo ...[more]

PMID: 35957801

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Project description:ObjectiveMetabolic reprogramming is one of the hallmarks of cancer, but metabolic pathway activity-related subtypes of hepatocellular carcinoma (HCC) have not been identified.MethodsBased on the quantification results of 41 metabolic pathway activities by gene set variation analysis, the training cohort (n = 609, merged by TCGA and GSE14520) was clustered into three subtypes (C1, C2, and C3) with the nonnegative matrix factorization method. Totally 1371 differentially expressed genes among C1, C2, and C3 were identified, and an 8-gene risk score was established by univariable Cox regression analysis, least absolute shrinkage and selection operator method, and multivariable Cox regression analysis.ResultsC1 had the strongest metabolic activity, good prognosis, the highest CTNNB1 mutation rate, with massive infiltration of eosinophils and natural killer cells. C2 had the weakest metabolic activity, poor prognosis, was younger, was inclined to vascular invasion and advanced stage, had the highest TP53 mutation rate, exhibited a higher expression level of immune checkpoints, accompanied by massive infiltration of regulatory T cells. C3 had moderate metabolic activity and prognosis, the highest LRP1B mutation rate, and a higher infiltration level of neutrophils and macrophages. Internal cohorts (TCGA, n = 370; GSE14520, n = 239), external cohorts (ICGC, n = 231; GSE116174, n = 64), and clinical subgroup validation showed that the risk score was applicable for patients with diverse clinical features and was effective in predicting the prognosis and malignant progression of patients with HCC. Compared with the low-risk group, the high-risk group had a poor prognosis, enhanced cancer stem cell characteristics, activated DNA damage repair, weakened metabolic activity, cytolytic activity, and interferon response.ConclusionWe identified HCC subtypes from the perspective of metabolism-related pathway activity and proposed a robust prognostic signature for HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, the molecular mechanisms involved in HCC remain unclear and are in urgent need of elucidation. Therefore, we sought to identify biomarkers in the prognosis of HCC through an integrated bioinformatics analysis.MethodsMessenger RNA (mRNA) expression profiles were obtained from the Gene Expression Omnibus database and The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) for the screening of common differentially expressed genes (DEGs). Function and pathway enrichment analysis, protein-protein interaction network construction and key gene identification were performed. The significance of key genes in HCC was validated by overall survival analysis and immunohistochemistry. Meanwhile, based on TCGA data, prognostic microRNAs (miRNAs) were decoded using univariable and multivariable Cox regression analysis, and their target genes were predicted by miRWalk.ResultsEleven hub genes (upregulated ASPM, AURKA, CCNB2, CDC20, PRC1 and TOP2A and downregulated AOX1, CAT, CYP2E1, CYP3A4 and HP) with the most interactions were considered as potential biomarkers in HCC and confirmed by overall survival analysis. Moreover, AURKA, PRC1, TOP2A, AOX1, CYP2E1, and CYP3A4 were considered candidate liver-biopsy markers for high risk of developing HCC and poor prognosis in HCC. Upregulation of hsa-mir-1269b, hsa-mir-518d, hsa-mir-548aq, hsa-mir-548f-1, and hsa-mir-6728, and downregulation of hsa-mir-139 and hsa-mir-4800 were determined to be risk factors of poor prognosis, and most of these miRNAs have strong potential to help regulate the expression of key genes.ConclusionsThis study undertook the first large-scale integrated bioinformatics analysis of the data from Illumina BeadArray platforms and the TCGA database. With a comprehensive analysis of transcriptional alterations, including mRNAs and miRNAs, in HCC, our study presented candidate biomarkers for the surveillance and prognosis of the disease, and also identified novel therapeutic targets at the molecular and pathway levels.

Dataset Information

Comprehensive Analysis of Histone Modifications in Hepatocellular Carcinoma Reveals Different Subtypes and Key Prognostic Models.

Publications

Comprehensive Analysis of Histone Modifications in Hepatocellular Carcinoma Reveals Different Subtypes and Key Prognostic Models.

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