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Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma.

ABSTRACT: Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and high mortality worldwide. DNA methylation, one of the most common epigenetic changes, might serve a vital regulatory role in cancer. Methods: To identify categories based on DNA methylation data, consensus clustering was employed. The risk signature was yielded by systematic bioinformatics analyses based on the remarkably methylated CpG sites of cluster 1. Kaplan-Meier analysis, variable regression analysis, and ROC curve analysis were further conducted to validate the prognosis predictive ability of risk signature. Gene set enrichment analysis (GSEA) was performed for functional annotation. To uncover the context of tumor immune microenvironment (TIME) of HCC, we employed the ssGSEA algorithm and CIBERSORT method and performed TIMER database exploration and single-cell RNA sequencing analysis. Additionally, quantitative real-time polymerase chain reaction was employed to determine the LRRC41 expression and preliminarily explore the latent role of LRRC41 in prognostic prediction. Finally, mutation data were analyzed by employing the "maftools" package to delineate the tumor mutation burden (TMB). Results: HCC samples were assigned into seven subtypes with different overall survival and methylation levels based on 5'-cytosine-phosphate-guanine-3' (CpG) sites. The risk prognostic signature including two candidate genes (LRRC41 and KIAA1429) exhibited robust prognostic predictive accuracy, which was validated in the external testing cohort. Then, the risk score was significantly correlated with the TIME and immune checkpoint blockade (ICB)-related genes. Besides, a prognostic nomogram based on the risk score and clinical stage presented powerful prognostic ability. Additionally, LRRC41 with prognostic value was corroborated to be closely associated with TIME characterization in both expression and methylation levels. Subsequently, the correlation regulatory network uncovered the potential targets of LRRC41 and KIAA1429. Finally, the methylation level of KIAA1429 was correlated with gene mutation status. Conclusion: In summary, this is the first to identify HCC samples into distinct clusters according to DNA methylation and yield the CpG-based prognostic signature and quantitative nomogram to precisely predict prognosis. And the pivotal player of DNA methylation of genes in the TIME and TMB status was explored, contributing to clinical decision-making and personalized prognosis monitoring of HCC.

SUBMITTER: Xu Q

PROVIDER: S-EPMC8187884 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatocellular carcinoma (HCC) ranks the sixth prevalent tumors with high mortality globally. Alternative splicing (AS) drives protein diversity, the imbalance of which might act an important factor in tumorigenesis. This study aimed to construct of AS-based prognostic signature and elucidate the role in tumor immune microenvironment (TIME) and immunotherapy in HCC.MethodsUnivariate Cox regression analysis was performed to determine the prognosis-related AS events and gene set enrichment analysis (GSEA) was employed for functional annotation, followed by the development of prognostic signatures using univariate Cox, LASSO and multivariate Cox regression. K-M survival analysis, proportional hazards model, and ROC curves were conducted to validate prognostic value. ESTIMATE R package, ssGSEA algorithm and CIBERSORT method and TIMER database exploration were performed to uncover the context of TIME in HCC. Quantitative real-time polymerase chain reaction was implemented to detect ZDHHC16 mRNA expression. Cytoscape software 3.8.0 were employed to visualize AS-splicing factors (SFs) regulatory networks.ResultsA total of 3294 AS events associated with survival of HCC patients were screened. Based on splicing subtypes, eight AS prognostic signature with robust prognostic predictive accuracy were constructed. Furthermore, quantitative prognostic nomogram was developed and exhibited robust validity in prognostic prediction. Besides, the consolidated signature was significantly correlated with TIME diversity and ICB-related genes. ZDHHC16 presented promising prospect as prognostic factor in HCC. Finally, the splicing regulatory network uncovered the potential functions of splicing factors (SFs).ConclusionHerein, exploration of AS patterns may provide novel and robust indicators (i.e., risk signature, prognostic nomogram, etc.,) for prognostic prediction of HCC. The AS-SF networks could open up new approach for investigation of potential regulatory mechanisms. And pivotal players of AS events in context of TIME and immunotherapy efficiency were revealed, contributing to clinical decision-making and personalized prognosis monitoring of HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) is an inflammation-related malignancy influenced by the immune microenvironment, such as immune tolerance and evasion. HFUN14 domain-with protein 1 (FUNDC1) is a necessary mitochondrial outer membrane protein, functioning as a receptor for hypoxia-caused mitophagy, which is related to human immunity. The relationship between HCC and FUNDC1 in terms of prognosis and immunology was demonstrated in the current investigation. Even so, the function of FUNDC1 in liver cancer is yet unknown.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were utilized for examining if FUNDC1 expression is associated with clinicopathological characteristics and prognosis. Genetic changes (mutation), DNA methylation, and their relationship with patient prognosis were identified by cBioPortal and MethSurv. Utilizing the Tumor Immune Estimation Resource (TIMER), immune checkpoints, infiltration, and immune cell biomarkers were analyzed. Utilizing the STRING database, the network of protein-protein interactions was created. Using Gene Set Enrichment Analysis, the FUNDC1 biological roles were determined (GSEA).ResultsFUNDC1 elevation was significantly linked with gender (p < 0.001), tumor stage (p = 0.01349), tumor grade (p < 0.001), and alpha-fetoprotein (AFP) (p < 0.001) levels in HCC. It was illustrated by ROC curve analysis that FUNDC1 had a significant diagnostic and prognostic value. The FUNDC1 genetic change rate was 0.6%. Four out of 6 DNA methylation CpG sites were associated with the HCC prognosis. FUNDC1 is associated strongly with immune cell infiltration in HCC. Moreover, FUNDC1 was positively related to immune checkpoints such as mutant-allele tumor heterogeneity (MATH) (p < 0.001), ploidy (p < 0.05), homologous recombination defect (HRD) (p < 0.001), and loss of heterozygosity (LOH). GSEA revealed significant FUNDC1 enrichment in the cell cycle, hedgehog, and MAPK signaling pathways.ConclusionFUNDC1 is a mitophagy regulator that could be a therapeutic, prognostic, and putative diagnostic biomarker for HCC.

Project description:BackgroundThe immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment.Patients and methodsWe enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves.ResultsThe neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio.ConclusionsThe neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy.

Project description:As one of the members of the kinesin family, the role and potential mechanism of kinesin family member C1 (KIFC1) in the development of liver hepatocellular carcinoma (LIHC), especially in the immune infiltration, have not been fully elucidated. In this study, multiple databases and immunohistochemistry were employed to analyze the role and molecular mechanism including the immune infiltration of KIFC1 in LIHC. Generally, KIFC1 mRNA expression was overexpressed in LIHC tissues than normal tissues, and its protein was also highly expressed in the LIHC. KIFC1 mRNA expression was correlated with tumor grade and TNM staging, which was negatively correlated with overall survival and disease-free survival. Moreover, univariable and multivariate Cox analysis revealed that upregulated KIFC1 mRNA is an independent prognostic factor for LIHC. The KIFC1 promoter methylation level was negatively associated with KIFC1 mRNA expression and advanced stages and grade in LIHC. The different methylation sites of KIFC1 had a different effect on the prognosis of LIHC. Specifically, the KIFC1 mRNA expression level showed intense correlation with tumor immunity, such as tumor-infiltrating immune cells and immune scores as well as multiple immune-related genes. Moreover, KIFC1 co-expressed with some immune checkpoints and related to the responses to immune checkpoint blockade (ICB) and chemotherapies. Significant GO analysis showed that genes correlated with KIFC1 served as catalytic activity, acting on DNA, tubulin binding, histone binding, ATPase activity, and protein serine/threonine kinase activity. KEGG pathway analysis showed that these genes related to KIFC1 are mainly enriched in signal pathways such as cell cycle, spliceosome, pyrimidine metabolism, and RNA transport. Conclusively, KIFC1 was upregulated and displayed a prognostic value in LIHC. Moreover, KIFC1 may be involved in the LIHC progression partially through immune evasion and serve as a predictor of ICB therapies and chemotherapies.

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Immunological Significance of Prognostic DNA Methylation Sites in Hepatocellular Carcinoma.

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