Dataset Information

Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma.

ABSTRACT: Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases. Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD). Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely. Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.

SUBMITTER: De Re V

PROVIDER: S-EPMC6429030 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma.

De Re Valli V Tornesello Maria Lina ML De Zorzi Mariangela M Caggiari Laura L Pezzuto Francesca F Leone Patrizia P Racanelli Vito V Lauletta Gianfranco G Gragnani Laura L Buonadonna Angela A Vaccher Emanuela E Zignego Anna Linda AL Steffan Agostino A Buonaguro Franco M FM

Frontiers in microbiology 20190315

<b>Background and Aims:</b> Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases. <b>Methods:</b> Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular appr ...[more]

PMID: 30930876

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Project description:Background: Mitophagy has been found to play a significant part in the cancer process in a growing number of studies in recent years. However, there is still a lack of study on mitophagy-related genes' (MRGs) prognostic potential and clinical significance in hepatocellular carcinoma (HCC). Methods: We employed bioinformatics and statistical knowledge to examine the transcriptome data of HCC patients in the TCGA and GEO databases, with the goal of constructing a multigene predictive model. Then, we separated the patients into high- and low-risk groups based on the score. The model's dependability was determined using principal components analysis (PCA), survival analysis, independent prognostic analysis, and receiver operating characteristic (ROC) analysis. Following that, we examined the clinical correlations, pharmacological treatment sensitivity, immune checkpoint expression, and immunological correlations between patients in high and low risk groups. Finally, we evaluated the variations in gene expression between high- and low-risk groups and further analyzed the network core genes using protein-protein interaction network analysis. Results: Prognostic models were built using eight genes (OPTN, ATG12, CSNK2A2, MFN1, PGAM5, SQSTM1, TOMM22, TOMM5). During validation, the prognostic model demonstrated high reliability, indicating that it could accurately predict the prognosis of HCC patients. Additionally, we discovered that typical HCC treatment medicines had varying impacts on patients classified as high or low risk, and that individuals classified as high risk are more likely to fail immunotherapy. Additionally, the high-risk group expressed more immunological checkpoints. The immunological status of patients in different risk categories varies as well, and patients with a high-risk score have a diminished ability to fight cancer. Finally, PPI analysis identified ten related genes with potential for research. Conclusion: Our prognostic model had good and reliable predictive ability, as well as clinical diagnosis and treatment guiding significance. Eight prognostic MRGs and ten network core genes merited further investigation.

Project description:ObjectiveThis study aims to build a prognostic model of hepatocellular carcinoma (HCC) with ferroptosis-associated genes and explore their molecular function.MethodsGene expression data and clinical information were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and the International Cancer Genome Consortium (ICGC). A ferroptosis-associated gene set was obtained from the FerrDb database to identify differentially expressed genes. Then, we performed pathway enrichment analysis and immune infiltration analysis. A combined model based on ferroptosis-associated genes for predicting the overall survival of HCC was built by univariate and multivariate Cox regression analyses. Quantitative real-time polymerase chain reaction, Western blotting, colony formation, CCK-8, and EdU incorporation assays were performed to clarify the function of CAPG in the regulation of cell proliferation in human HCC. Ferroptosis was evaluated by glutathione (GSH), malondialdehyde (MDA), and total iron detection.ResultsForty-nine ferroptosis-related genes were significantly correlated with HCC, 19 of which had prognostic significance. CAPG, SLC7A11 and SQSTM1 were used to construct a novel risk model. The areas under the curves (AUCs) were 0.746 and 0.720 (1 year) in the training and validation groups, respectively. The survival analysis indicated that patients with high risk scores exhibited worse survival in the training and validation groups. The risk score was also identified as an independent prognostic factor of overall survival (OS), which established and validated the predictive abilities of the nomogram. The risk score was also significantly correlated with the expression of immune checkpoint genes. In vitro data showed that CAPG knockdown dramatically suppressed HCC cell proliferation, and the underlying molecular mechanisms might be that the silencing of CAPG reduced the expression of SLC7A11 and promoted ferroptosis.ConclusionThe established risk model can be used to predict the prognosis of HCC. At the mechanistic level, CAPG may drive HCC progression by regulating SLC7A11, and ferroptosis activation in HCC patients with high CAPG expression may serve as a potential therapeutic strategy.

Dataset Information

Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma.

Publications

Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma.

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