Dataset Information

Identification of TP53 mutation associated-immunotype and prediction of survival in patients with hepatocellular carcinoma.

ABSTRACT: Background:Stratification of tumors is necessary to achieve better clinical outcomes. Hepatocellular carcinoma (HCC) is commonly associated with mutation of the TP53 gene and heterogeneity in immune cell content. However, TP53 mutation-associated immunotype of HCC has not been reported yet. This study aimed to identify the TP53 mutation-associated immunotype in HCC. Methods:The mutation annotation format (MAF) document, mRNA expression data, and clinical data of HCC patients were downloaded from the publicly available The Cancer Genome Atlas (TCGA) data portal. Data from 332 HCC patients were analyzed in this study. Infiltrating immune cells were evaluated by the well-known CIBERSORT method. Additional mutation data of HCC patients were downloaded from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Results:The TP53 gene harbored the highest frequency of mutations in HCC patients. Consequently, five lethal features, including TP53 mutations, were screened by least absolute shrinkage and selector operation (LASSO)-COX regression, according to TP53 mutations and 22 infiltrating immune cells. Two distinct subgroups of HCC were identified, namely, immunotypes A and B. Furthermore, the expression levels of co-inhibitory immune checkpoints were significantly upregulated, and the gene ontology (GO) terms or pathways to boost immune responses were found to be inhibited in the immunotype B subgroup compared to that in the immunotype A subgroup. Finally, we proved immunotype to be an independent adverse prognostic factor that contributed to improvement in the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment. Conclusions:Two distinct immunotypes of HCC, in terms of prognosis, phenotype, and function, were identified and the traditional understanding of intratumoralCD8+ T cells was subverted. Moreover, the identified immunotypes contributed to improving the predictive accuracy of the immunotype-based model and helped in avoiding excessive medical treatment in some HCC patients.

SUBMITTER: Shi M

PROVIDER: S-EPMC7186599 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of <i>TP53</i> mutation associated-immunotype and prediction of survival in patients with hepatocellular carcinoma.

Shi Muqi M Wang Yan Y Tang Weidong W Cui Xiaohong X Wu Han H Tang Yijie Y Wang Peng P Wu Wei W Zhang Haijian H

Annals of translational medicine 20200301 6

<h4>Background</h4>Stratification of tumors is necessary to achieve better clinical outcomes. Hepatocellular carcinoma (HCC) is commonly associated with mutation of the <i>TP53</i> gene and heterogeneity in immune cell content. However, <i>TP53</i> mutation-associated immunotype of HCC has not been reported yet. This study aimed to identify the <i>TP53</i> mutation-associated immunotype in HCC.<h4>Methods</h4>The mutation annotation format (MAF) document, mRNA expression data, and clinical data ...[more]

PMID: 32355765

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Project description:Exosome DNA (exoDNA) can be used for liquid biopsy. This study was the first to use droplet digital PCR (ddPCR) to detect tumor-specific mutations in exoDNA and to evaluate the prognosis of hepatocellular carcinoma (HCC) patients. 60 HCC patients were enrolled in the study. We used ddPCR to detect c.747 G > T mutation in TP53 gene. We analyzed the correlation between detectable mutation in exoDNA and clinicopathologic characteristics using Multivariate logistics regression analysis. We performed Cox regression to assess the correlation between mutation frequency (mutant droplets/total droplets, MD/TD) and prognostic. We found that 48 of 60 patients had c.747 G > T mutation in TP53 gene in exoDNA (80.0%). We found that detectable mutation in exoDNA and age were associated with microvascular invasion (MVI) (P < .01). The ROC curve analysis revealed that the best cutoff value of mutation frequency to predict MVI was 67% (sensitivity 48.15%, specificity 93.94%,), the corresponding AUC was 0.761 (95%CI, 0.640-0.866; P < .01). Furthermore, we found that patients suffered high-frequency mutation (>67%) had shorted median recurrence-free survival (RFS) with 63 days (range, 53-202 days), compared with 368 days (range, 51-576 days) for patients with low-frequency mutation (<67%) (HR:4.61; 95% CI, 1.70-12.48; P = 0 .003). We also found that high-frequency mutation was associated with poor prognosis though patients had better pathological characteristics, such as AFP (<400 ng/mL), Liver cirrhosis (Negative), Tumor thrombus (Negative), Tumor numbers (Single) and Post-operation TACE (Executed). We provided evidence that the mutations in exoDNA might be used to predict patients with poor RFS.Abbreviations: TP53: Tumor protein p53; ExoDNA: Exosomal DNA; HCC: Hepatocellular carcinoma; ddPCR: Droplet digital Polymerase Chain Reaction (PCR); MD/TD: The ratio of mutant droplets/total droplets; AFP: Alpha-fetoprotein; MVI: Microvascular invasion; RFS: Recurrence-free survival.

Project description:Hepatocellular carcinoma (HCC) samples were clustered into three energy metabolism-related molecular subtypes (C1, C2, and C3) with different prognosis using the gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). HCC energy metabolism-related molecular subtype analysis was conducted based on the 594 energy metabolism genes. Differential expression analysis yielded 576 differentially expressed genes (DEGs) among the three subtypes, which were closely related to HCC progression. Six genes were finally selected from the 576 DEGs through LASSO-Cox regression and used in constructing a six-gene signature-associated prognostic risk model, which was validated using the TCGA internal and three GEO external validation cohorts. The risk model showed that high ANLN, ENTPD2, TRIP13, PLAC8, and G6PD expression levels were associated with bad prognosis, and high expression of ADH1C was associated with a good prognosis. The validation results showed that our risk model had a high distinguishing ability of prognosis in HCC patients. The four enriched pathways of the risk model were obtained by gene set enrichment analysis (GSEA) and found to be associated with the tumorigenesis and development of HCC, including the cell cycle, Wnt signaling pathway, drug metabolism cytochrome P450, and primary bile acid biosynthesis. The risk score calculated from the established risk model in 204 samples and other clinical characteristics were used in building a nomogram with a good prognostic prediction ability (C-index = 0.746, 95% CI = 0.714-0.777). The area under the curves (AUCs) of the nomogram model in 1-, 2-, and 3-years were 0.82, 0.77, and 0.79, respectively. Then, qRT-PCR and immunohistochemistry were used to validate the mRNA expression levels of the six genes, and significant differences in mRNA and gene expression were observed among the tumor and adjacent tissues. Overall, our study divided HCC patients into three energy metabolism-related molecular subtypes with different prognosis. Then, a risk model with a good performance in prognostic prediction was built using the TCGA dataset. This model can be used as an independent prognostic evaluation index for HCC patients.

Project description:Background: TP53 mutations are the most frequent mutations in hepatocellular carcinoma (HCC) and affect the occurrence and development of this cancer type. Therefore, it is essential to clarify the function and mechanism of TP53 mutations in HCC. Methods: We performed a sequence of bioinformatic analyses to elucidate the characteristics of TP53 mutations in HCC. We downloaded the data of hepatocellular carcinoma from The Cancer Genome Atlas database and used different R packages for serial analyses, including gene mutation analysis, copy number variation analysis, analysis of the tumor mutational burden and microsatellite instability, differential gene expression analysis, and functional enrichment analysis of TP53 mutations, and performed gene set enrichment analysis. We established a protein-protein interaction network using the STRING online database and used the Cytoscape software for network visualization, and hub gene screening. In addition, we performed anticancer drug sensitivity analysis using data from the Genomics of Drug Sensitivity in Cancer. Immune infiltration and prognosis analyses were also performed. Results: Missense mutations accounted for a great proportion of HCC mutations, the frequency of single nucleotide polymorphisms was high, and C > T was the most common form of single nucleotide variations. TP53 had a mutation rate of 30% and was the most commonly mutated gene in HCC. In the TP53 mutant group, the tumor mutational burden (p < 0.001), drug sensitivity (p < 0.05), ESTIMATE score (p = 0.038), and stromal score (p < 0.001) dramatically decreased. The Cytoscape software screened ten hub genes, including CT45A1, XAGE1B, CT55, GAGE2A, PASD1, MAGEA4, CTAG2, MAGEA10, MAGEC1, and SAGE1. The prognostic model showed a poor prognosis in the TP53 mutation group compared with that in the wild-type group (overall survival, p = 0.023). Univariate and multivariate cox regression analyses revealed that TP53 mutation was an independent risk factor for the prognosis of HCC patients (p <0.05). The constructed prognostic model had a favorable forecast value for the prognosis of HCC patients at 1 and 3 years (1-year AUC = 0.752, 3-years AUC = 0.702). Conclusion: This study further deepened our understanding of TP53-mutated HCC, provided new insights into a precise individualized therapy for HCC, and has particular significance for prognosis prediction.

Dataset Information

Identification of TP53 mutation associated-immunotype and prediction of survival in patients with hepatocellular carcinoma.

Publications

Identification of <i>TP53</i> mutation associated-immunotype and prediction of survival in patients with hepatocellular carcinoma.

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