Pyroptosis related genes signature predicts prognosis and immune infiltration of tumor microenvironment in hepatocellular carcinoma.

Little is known on the relationship between the expression of pyroptosis related genes (PRGs) and prognosis of hepatocellular carcinoma (HCC). In this study, a specific PRGs prognostic model was developed with an aim to improve therapeutic efficiency among HCC patients. In total, 42 PRGs that were differentially expressed between HCC tissues and adjacent tissues and we exhibited the mutation frequency, classification, the location of copy number variation (CNV) alteration and the CNV variation frequency of PRGs. Two clusters were distinguished by the consensus clustering analysis based on the 42 differentially expressed genes (DEGs). There were significant differences in clinical features including T stage, grade, gender, and stage among different clusters. Kaplan-Meier curve analysis showed that cluster 1 had a better prognosis than cluster 2. The prognostic value of PRGs for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. Based on the univariate analysis and multivariate analysis, a 10-gene signature was built and all HCC patients in the TCGA cohort were divided into low-risk group and high-risk group. HCC patients in the high-risk group showed significantly lower survival possibilities than those in the low-risk group (P < 0.001). Utilizing the median risk score from the TCGA cohort, HCC patients from International Cancer Genome Consortium (ICGC)-LIRI-JP cohort and Gene Expression Omnibus (GEO) cohort (GSE14520) were divided into two risk subgroups. The result showed that overall survival (OS) time was decreased in the high-risk group. Combined with the clinical characteristics, the risk score was an independent factor for predicting the OS of HCC patients. Then, ROC curve and survival analysis were performed to evaluate the prognostic prediction value of the model. Finally, we constructed a PRGs clinical characteristics nomogram to further predict HCC patient survival probability. There were significant differences in immune cell infiltration, GSEA enrichment pathway, IC50 of chemotherapeutics, PRGs mutation frequency between high-risk group and low-risk group. This work suggests PRGs signature played a crucial role in predicting the prognosis, infiltration of cancer microenvironment, and sensitivity of chemotherapeutic agents.

Fang G ，Zhang Q ，Fan J ，Li H ，Ding Z ，Fu J ，Wu Y ，Zeng Y ，Liu J ... -  《BMC CANCER》

Comprehensive genomic signature of pyroptosis-related genes and relevant characterization in hepatocellular carcinoma.

Wang S ，Gao S ，Shan L ，Qian X ，Luan J ，Lv X ... -  《PeerJ》

A pyroptosis-related gene signature predicts prognosis and immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a very poor prognosis. Pyroptosis is an inflammatory form of cell death and plays an important role in cancer development. The prognostic value of pyroptosis-related genes (PRGs) in HCC has not been studied extensively. Unsupervised consensus clustering analysis was performed to identify two subtypes based on the expression profiles of prognostic PRGs in the The Cancer Genome Atlas (TCGA) database, and the differences between the two subtypes were compared. A prognostic model based on four PRGs was established by further least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox regression analysis. Two subtypes (clusters 1 and 2) were identified by consensus clustering based on prognostic PRGs in HCC. Survival outcomes, biological function, genomic alterations, immune cell infiltration, and immune checkpoint genes were compared between the subtypes. Cluster 2 had a worse survival outcome than cluster 1. Cluster 2 was enriched for hallmarks of cancer progression, TP53 mutation, tumor-promoting immune cells, and immune checkpoint genes, which may contribute to the poor prognosis. A prognostic risk signature that predicted the overall survival (OS) of patients was constructed and validated. Consequently, a risk score was calculated for each patient. Combined with the clinical characteristics, the risk score was found to be an independent prognostic factor for survival of HCC patients. Further analysis revealed that the risk score was closely associated with the levels of immune cell infiltration and the expression profiles of immune checkpoint genes. Collectively, our study established a prognostic risk signature for HCC and revealed a significant correlation between pyroptosis and the HCC immune microenvironment.

Jin Y ，Pu X ，Ping D ，Huang C ，Ding G ，Cao L ... -  《World Journal of Surgical Oncology》

Cuproptosis-Related Signature Predicts the Prognosis, Tumor Microenvironment, and Drug Sensitivity of Hepatocellular Carcinoma.

Copper (Cu) metabolism is strongly associated with liver disease. Cuproptosis is a novel format of cell death, and cuproptosis-related genes (CRGs) were identified. However, the role of CRGs in Hepatocellular Carcinoma (HCC) remains unknown. The mRNA transcriptome profiling data, somatic mutation data, and copy number gene level data of The Cancer Genome Atlas-Liver Hepatocellular Carcinoma project (TCGA-LIHC) were downloaded for subsequent analysis. Molecular characterization analysis of CRGs, including differential gene expression analysis, mutation analysis, copy number variation (CNV) analysis, Kaplan-Meier analysis, and immune regulator prioritization analysis, was implemented. The nonnegative matrix factorization (NMF) approach was used to identify the CRG-related molecular subtypes. Principal component analysis was adopted to verify the robustness and reliability of the molecular subtype. The least absolute shrinkage and selection operator regression analysis was performed to construct the prognostic signature based on differentially expressed genes between molecular subtypes. The survival characteristics of the molecular subtype and the signature were analyzed. The Gene Set Variation Analysis was performed for functional annotation. The immune landscape analysis, including immune checkpoint gene analysis, single sample gene set enrichment analysis, tumor immune dysfunction and exclusion (TIDE) analysis, immune infiltration cell, and tumor mutation burden analysis (TMB), was conducted. The ability of the signature to predict conventional anti-HCC agent responses was evaluated. The signature was validated in the LIRI-JP cohort and the IMvigor210 cohort. A total of 13 CRGs are differentially expressed between the tumor and normal samples, while the mutation of CRGs in HCC is infrequent. The expression of CRGs is associated with the CNV level. Fourteen CRGs are associated with the prognosis of HCC. Two clusters were identified and HCC patients were divided into 2 groups with a cutoff risk score value of 1.570. HCC patients in the C1 cluster and high-risk have a worse prognosis. The area under the receiver operating characteristic curve for predicting 1-, 2-, and 3-year overall survival is 0.775, 0.768, and 0.757 in the TCGA-LIHC cohort, and 0.811, 0.741, and 0.775 in the LIRI-JP cohort. Multivariate Cox regression analysis indicates that the signature is an independent prognostic factor. Pathways involved in metabolism and gene stability and immune infiltration cells are significantly enriched. Immune checkpoint genes are highly expressed in the C1 cluster. TMB is positively correlated with the risk score. HCC patients in the high-risk group are more likely to benefit from conventional anti-HCC agents and immune checkpoint inhibitor therapies. The molecular characterization of CRGs in HCC is presented in this study, and a successful prognostic signature for HCC based on the cuproptosis-related molecular subtype was constructed.

Qi X ，Guo J ，Chen G ，Fang C ，Hu L ，Li J ，Zhang C ... -  《-》

Combination of ferroptosis and pyroptosis to construct a prognostic classifier and predict immune landscape, chemotherapeutic efficacy and immunosuppressive molecules in hepatocellular carcinoma.

The induction of ferroptosis and pyroptosis has been highlighted as a novel approach to decide cancer cell fate. However, few studies have systematically explored the role of combining these two novel cell death modalities in hepatocellular carcinoma  (HCC). Ferroptosis-related genes (FRGs) and pyroptosis-related genes (PRGs) were retrieved and downloaded from FerrDb and GeneCards database, respectively. A prognostic classifier integrating with prognostic differentially expressed FRGs and PRGs was constructed by the least absolute shrinkage and selection operator (LASSO) algorithm in the TCGA-LIHC dataset and verified using the ICGC (LIRI-JP) dataset. A total of 194 differentially expressed FRGs and PRGs were identified and named as differentially expressed genes (DEGs) and, out of them 79 were found dramatically correlated with prognosis in HCC. Based on 13 key DEGs with prognostic value, a novel expression signature was constructed and used to stratify HCC patients into 2 groups. Kaplan-Meier analysis demonstrated that high-risk patients had a more dismal prognosis. Receiver operating characteristic curve (ROC) and multivariate Cox analysis confirmed its predictive power and independent characteristic. Immune profile analysis demonstrated that high-risk group had prominent upregulation of immunosuppressive cells, including macrophages, Th2_cells and Treg. The correlation analysis between this signature and immunosuppressive molecules, Immunophenoscore (IPS) and chemotherapeutic efficacy demonstrated that low-risk group had a higher  IC50 of cisplatin, mitomycin and doxorubicin and negatively related with CTLA4, HAVCR2, LAG3, PDCD1, TIGIT and ICIs treatment represented by CTLA4-/PD-1-, CTLA4 + /PD-1-, CTLA4-/PD-1 + . In this research, a novel expression signature was identified based on FRGs and PRGs in HCC, and this signature could be used to predict prognosis and select patients potentially benefiting from immunotherapies and chemotherapy.

Xu L ，Zheng Q ，Liu W 《BMC CANCER》