scholarly journals A Novel Pyroptosis-related Genes Prognostic Signature Affects the Immune Infiltration Patterns in Hepatocellular Carcinoma

Author(s):  
Yiqun Jin ◽  
Bai. Xue-song

Abstract PurposePyroptosis is an inflammatory form of cell death associated with tumorigenesis and progression. However, the prognostic value of pyroptosis-related genes (PRGs) in hepatocellular carcinoma (HCC) have not been elucidated.MethodsWe downloaded mRNA expression profiles and clinical information from TCGA and ICGC database. Then, differently expressed PRGs were screened to construct a multigene prognostic signature by least absolute contraction and selection operator (LASSO) Cox regression method in TCGA cohort. Date from ICGC was used to validate the robustness of this signature. Kaplan-Meier analysis was used to compare overall survival (OS) between high- and low-risk group. Univariate and multivariate Cox analysis were performed to identify the independent prognostic value of the signature. Gene set enrichment analysis (GSEA) was utilized to conduct GO and KEGG analysis. Single-sample gene set enrichment analysis was implemented to assess the immune cell infiltration and immune-related function. TIDE algorithm evaluated the significance of this signature in predicting immunotherapeutic sensitivity. ResultsAn 8-PRGs prognostic model was established. The OS of low-risk group was significantly increased compared to high-risk group. Receiver operating characteristic curve showed the model had a good prognostic predictive accuracy. Cox regression analysis proved the model an independent predictor for OS in HCC. GSEA indicated that the risk score was associated with immune response. Furthermore, different subgroups exhibited different immunoinfiltration patterns, different immune-checkpoint levels and different potential responses for immune-checkpoint blockade therapy.ConclusionAn 8-PRGs signature can predict the prognosis of HCC patients and may act as an immunotherapeutic potential target for HCC.

2021 ◽  
Author(s):  
Yanjia Hu ◽  
Jing Zhang ◽  
Jing Chen

Abstract Background Hypoxia-related long non-coding RNAs (lncRNAs) have been proven to play a role in multiple cancers and can serve as prognostic markers. Lower-grade gliomas (LGGs) are characterized by large heterogeneity. Methods This study aimed to construct a hypoxia-related lncRNA signature for predicting the prognosis of LGG patients. Transcriptome and clinical data of LGG patients were obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). LGG cohort in TCGA was chosen as training set and LGG cohorts in CGGA served as validation sets. A prognostic signature consisting of fourteen hypoxia-related lncRNAs was constructed using univariate and LASSO Cox regression. A risk score formula involving the fourteen lncRNAs was developed to calculate the risk score and patients were classified into high- and low-risk groups based on cutoff. Kaplan-Meier survival analysis was used to compare the survival between two groups. Cox regression analysis was used to determine whether risk score was an independent prognostic factor. A nomogram was then constructed based on independent prognostic factors and assessed by C-index and calibration plot. Gene set enrichment analysis and immune cell infiltration analysis were performed to uncover further mechanisms of this lncRNA signature. Results LGG patients with high risk had poorer prognosis than those with low risk in both training and validation sets. Recipient operating characteristic curves showed good performance of the prognostic signature. Univariate and multivariate Cox regression confirmed that the established lncRNA signature was an independent prognostic factor. C-index and calibration plots showed good predictive performance of nomogram. Gene set enrichment analysis showed that genes in the high-risk group were enriched in apoptosis, cell adhesion, pathways in cancer, hypoxia etc. Immune cells were higher in high-risk group. Conclusion The present study showed the value of the 14-lncRNA signature in predicting survival of LGGs and these 14 lncRNAs could be further investigated to reveal more mechanisms involved in gliomas.


2021 ◽  
Author(s):  
Yong Lv ◽  
ShuGuang Jin ◽  
Bo Xiang

Abstract BackgroundTreatment of neuroblastoma is evolving toward precision medicine. LncRNAs can be used as prognostic biomarkers in many types of cancer.MethodsBased on the RNA-seq data from GSE49710, we built a lncRNAs-based risk score using the least absolute shrinkage and selection operation (LASSO) regression. Cox regression, receiver operating characteristic curves were used to evaluate the association of the LASSO risk score with overall survival. Nomograms were created and then validated in an external cohort from TARGET database. Gene set enrichment analysis was performed to identify the significantly changed biological pathways. ResultsThe 16-lncRNAs-based LASSO risk score was used to separate patients into high-risk and low-risk groups. In GSE49710 cohort, the high-risk group exhibited a poorer OS than those in the low-risk group (P<0.001). Moreover, multivariate Cox regression analysis demonstrated that LASSO risk score was an independent risk factor (HR=6.201;95%CI:2.536-15.16). The similar prognostic powers of the 16-lncRNAs were also achieved in the external cohort and in stratified analysis. In addition, a nomogram was established and worked well both in the internal validation cohort (C-index=0.831) and external validation cohort (C-index=0.773). The calibration plot indicated the good clinical utility of the nomogram. Gene set enrichment analysis (GSEA) indicated that high-risk group was related with cancer recurrence, metastasis and inflammatory associated pathways.ConclusionThe lncRNA-based LASSO risk score is a promising and potential prognostic tool in predicting the survival of patients with neuroblastoma. The nomogram combined the lncRNAs and clinical parameters allows for accurate risk assessment in guiding clinical management.


2021 ◽  
Vol 11 ◽  
Author(s):  
Junyu Huo ◽  
Liqun Wu ◽  
Yunjin Zang

BackgroundThe high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood.Material and ApproachThis study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan–Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis.ResultsA prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression.ConclusionOur study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.


2020 ◽  
Author(s):  
Andi Ma ◽  
Yukai Sun ◽  
Racheal O. Ogbodu ◽  
Ling Xiao ◽  
Haibing Deng ◽  
...  

Abstract Background: It is well known that long non-coding RNAs (lncRNAs) play a vital role in cancer. We aimed to explore the prognostic value of potential immune-related lncRNAs in hepatocellular carcinoma (HCC). Methods: Validated the established lncRNA signature of 343 patients with HCC from The Cancer Genome Atlas (TCGA) and 81 samples from Gene Expression Omnibus (GEO). Immune-related lncRNAs for HCC prognosis were evaluated using Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analyses. LASSO analysis was performed to calculate a risk score formula to explore the difference in overall survival between high- and low-risk groups in TCGA, which was verified using GEO, Gene Ontology (GO), and pathway-enrichment analysis. These analyses were used to identify the function of screened genes and construct a co-expression network of these genes. Results: Using computational difference algorithms and lasso Cox regression analysis, the differentially expressed and survival-related immune-related genes (IRGs) among patients with HCC were established as five novel immune-related lncRNA signatures (AC099850.3, AL031985.3, PRRT3-AS1, AC023157.3, MSC-AS1). Patients in the low‐risk group showed significantly better survival than patients in the high‐risk group ( P = 3.033e−05). The signature identified can be an effective prognostic factor to predict patient survival. The nomogram showed some clinical net benefits predicted by overall survival. In order to explore its underlying mechanism, several methods of enrichment were elucidated using Gene Set Enrichment Analysis. Conclusion: Identifying five immune-related lncRNA signatures has important clinical implications for predicting patient outcome and guiding tailored therapy for patients with HCC with further prospective validation.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhijie Xu ◽  
Bi Peng ◽  
Qiuju Liang ◽  
Xi Chen ◽  
Yuan Cai ◽  
...  

Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson’s test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman’s correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.


2020 ◽  
Author(s):  
Hui Wang ◽  
Xiaoling Ma ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  

Abstract Background: Autophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC.Methods: First, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariat, LASSO, and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, gene set enrichment and somatic mutation analyses were also used for these prognostic autophagy-related genes. Results: A total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into high-risk and low-risk groups (P<0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group. Gene set enrichment analysis revealed high risk score was associated with tumor initiation and progression associated pathways.Conclusions: Based on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics.


2020 ◽  
Author(s):  
Hui Wang ◽  
Xiaoling Ma ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  

Abstract Background: Autophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC. Methods: First, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariat, LASSO, and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, gene set enrichment and somatic mutation analyses were also used for these prognostic autophagy-related genes. Results: A total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into high-risk and low-risk groups (P<0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group. Gene set enrichment analysis revealed high risk score was associated with tumor initiation and progression associated pathways. Conclusions: Based on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics.


2021 ◽  
Vol 12 ◽  
Author(s):  
Facai Zhang ◽  
Xiaoming Wang ◽  
Yunjin Bai ◽  
Huan Hu ◽  
Yubo Yang ◽  
...  

ObjectivesThis study aimed to develop and validate a hypoxia signature for predicting survival outcomes in patients with bladder cancer.MethodsWe downloaded the RNA sequence and the clinicopathologic data of the patients with bladder cancer from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/repository?facetTab=files) and the Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. Hypoxia genes were retrieved from the Molecular Signatures Database (https://www.gsea-msigdb.org/gsea/msigdb/index.jsp). Differentially expressed hypoxia-related genes were screened by univariate Cox regression analysis and Lasso regression analysis. Then, the selected genes constituted the hypoxia signature and were included in multivariate Cox regression to generate the risk scores. After that, we evaluate the predictive performance of this signature by multiple receiver operating characteristic (ROC) curves. The CIBERSORT tool was applied to investigate the relationship between the hypoxia signature and the immune cell infiltration, and the maftool was used to summarize and analyze the mutational data. Gene-set enrichment analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in both risk groups. Furthermore, we developed a model and presented it with a nomogram to predict survival outcomes in patients with bladder cancer.ResultsEight genes (AKAP12, ALDOB, CASP6, DTNA, HS3ST1, JUN, KDELR3, and STC1) were included in the hypoxia signature. The patients with higher risk scores showed worse overall survival time than the ones with lower risk scores in the training set (TCGA) and two external validation sets (GSE13507 and GSE32548). Immune infiltration analysis showed that two types of immune cells (M0 and M1 macrophages) had a significant infiltration in the high-risk group. Tumor mutation burden (TMB) analysis showed that the risk scores between the wild types and the mutation types of TP53, MUC16, RB1, and FGFR3 were significantly different. Gene-Set Enrichment Analysis (GSEA) showed that immune or cancer-associated pathways belonged to the high-risk groups and metabolism-related signal pathways were enriched into the low-risk group. Finally, we constructed a predictive model with risk score, age, and stage and validated its performance in GEO datasets.ConclusionWe successfully constructed and validated a novel hypoxia signature in bladder cancer, which could accurately predict patients’ prognosis.


2021 ◽  
Vol 7 ◽  
Author(s):  
Xiaoyu Deng ◽  
Qinghua Bi ◽  
Shihan Chen ◽  
Xianhua Chen ◽  
Shuhui Li ◽  
...  

Although great progresses have been made in the diagnosis and treatment of hepatocellular carcinoma (HCC), its prognostic marker remains controversial. In this current study, weighted correlation network analysis and Cox regression analysis showed significant prognostic value of five autophagy-related long non-coding RNAs (AR-lncRNAs) (including TMCC1-AS1, PLBD1-AS1, MKLN1-AS, LINC01063, and CYTOR) for HCC patients from data in The Cancer Genome Atlas. By using them, we constructed a five-AR-lncRNA prognostic signature, which accurately distinguished the high- and low-risk groups of HCC patients. All of the five AR lncRNAs were highly expressed in the high-risk group of HCC patients. This five-AR-lncRNA prognostic signature showed good area under the curve (AUC) value (AUC = 0.751) for the overall survival (OS) prediction in either all HCC patients or HCC patients stratified according to several clinical traits. A prognostic nomogram with this five-AR-lncRNA signature predicted the 3- and 5-year OS outcomes of HCC patients intuitively and accurately (concordance index = 0.745). By parallel comparison, this five-AR-lncRNA signature has better prognosis accuracy than the other three recently published signatures. Furthermore, we discovered the prediction ability of the signature on therapeutic outcomes of HCC patients, including chemotherapy and immunotherapeutic responses. Gene set enrichment analysis and gene mutation analysis revealed that dysregulated cell cycle pathway, purine metabolism, and TP53 mutation may play an important role in determining the OS outcomes of HCC patients in the high-risk group. Collectively, our study suggests a new five-AR-lncRNA prognostic signature for HCC patients.


2021 ◽  
Author(s):  
HUA HUANG ◽  
Shanshan Xu ◽  
Youran Li ◽  
Yunfei Gu ◽  
Lijiang Ji

Abstract Background: Colorectal cancer (CRC), the commonly seen malignancy, ranks the 3rd place among the causes of cancer-associated mortality. As suggested by more and more studies, long coding RNAs (lncRNAs) have been considered as prognostic biomarkers for CRC. But the significance of hypoxic lncRNAs in predicting CRC prognosis remains unclear.Methods: The gene expressed profiles for CRC cases were obtained based on the Cancer Genome Atlas (TCGA) and applied to estimate the hypoxia score using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Overall survival (OS) of high- and low-hypoxia score group was analyzed by the Kaplan–Meier (KM) plot. To identify differentially expressed lncRNAs (DELs) between two hypoxia score groups, this study carried out differential expression analysis, and then further integrated with the DELs between controls and CRC patients to generate the hypoxia-related lncRNAs for CRC. Besides, prognostic lncRNAs were screened by the univariate Cox regression, which were later utilized for constructing the prognosis nomogram for CRC by adopting the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, both accuracy and specificity of the constructed prognostic signature were detected through the receiver operating characteristic (ROC) analysis. Moreover, our constructed prognosis signature also was validated in the internal testing test. This study operated gene set enrichment analysis (GSEA) for exploring potential biological functions associated with the prognostic signature. Finally, the ceRNA network of the prognostic lncRNAs was constructed.Results: Among 2299 hypoxia-related lncRNAs of CRC in total, LINC00327, LINC00163, LINC00174, SYNPR-AS1, and MIR31HG were identified as prognostic lncRNAs by the univariate Cox regression, and adopted for constructing the prognosis signature for CRC. ROC analysis showed the predictive power and accuracy of the prognostic signature. Additionally, the GSEA revealed that ECM-receptor interaction, PI3K-Akt pathway, phagosome, and Hippo pathway were mostly associated with the high-risk group. 352 miRNAs-mRNAs pairs and 177 lncRNAs-miRNAs were predicted.Conclusion: To conclude , we identified 5 hypoxia-related lncRNAs to establish an accurate prognostic signature for CRC, providing important prognostic markers and therapeutic target.


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