International Cancer Genome Consortium Datasets Research Articles

Identification of immune cell-related prognostic genes characterized by a distinct microenvironment in hepatocellular carcinoma.

The development and progression of hepatocellular carcinoma (HCC) have been reported to be associated with immune-related genes and the tumor microenvironment. Nevertheless, there are not enough prognostic biomarkers and models available for clinical use. Based on seven prognostic genes, this study calculated overall survival in patients with HCC using a prognostic survival model and revealed the immune status of the tumor microenvironment (TME). To develop a novel immune cell-related prognostic model of HCC and depict the basic profile of the immune response in HCC. We obtained clinical information and gene expression data of HCC from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. TCGA and ICGC datasets were used for screening prognostic genes along with developing and validating a seven-gene prognostic survival model by weighted gene coexpression network analysis and least absolute shrinkage and selection operator regression with Cox regression. The relative analysis of tumor mutation burden (TMB), TME cell infiltration, immune checkpoints, immune therapy, and functional pathways was also performed based on prognostic genes. Seven prognostic genes were identified for signature construction. Survival receiver operating characteristic curve analysis showed the good performance of survival prediction. TMB could be regarded as an independent factor in HCC survival prediction. There was a significant difference in stromal score, immune score, and estimate score between the high-risk and low-risk groups stratified based on the risk score derived from the seven-gene prognostic model. Several immune checkpoints, including VTCN1 and TNFSF9, were found to be associated with the seven prognostic genes and risk score. Different combinations of checkpoint blockade targeting inhibitory CTLA4 and PD1 receptors and potential chemotherapy drugs hold great promise for specific HCC therapies. Potential pathways, such as cell cycle regulation and metabolism of some amino acids, were also identified and analyzed. The novel seven-gene (CYTH3, ENG, HTRA3, PDZD4, SAMD14, PGF, and PLN) prognostic model showed high predictive efficiency. The TMB analysis based on the seven genes could depict the basic profile of the immune response in HCC, which might be worthy of clinical application.

Development and Validation of the novel Cuproptosis- and Immune-related Signature for Predicting Prognosis in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma often results in late-stage diagnosis, leading to decreased treatment success. To improve prognosis, this study integrates cuproptosis with immune risk scoring models for HCC patients. Method: We identified differentially expressed genes connected to cuproptosis and immune responses using Pearson correlation. A risk signature was then constructed via LASSO regression, and its robustness was validated in the International Cancer Genome Consortium dataset. Additionally, qPCR confirmed findings in tumor and normal tissues. Results: Eight genes emerged as key prognostic markers from the 110 differentially expressed genes linked to cuproptosis and immunity. A risk-scoring model was developed using gene expression, effectively categorizing patients into low- or high-risk groups. Validated in the ICGC dataset, high-risk patients had significantly reduced survival times. Multivariate Cox regression affirmed the risk signature's independent predictive capability. A clinical nomogram based on the risk signature was generated. Notably, low-risk patients might benefit more from immune checkpoint inhibitors. qPCR and western blotting results substantiated our bioinformatics findings. Conclusions: The genetic risk signature linked to cuproptosis and immunity holds potential as a vital prognostic biomarker for Hepatocellular carcinoma, providing avenues for tailored therapeutic strategies.

Role for ubiquitin-specific protease 7 (USP7) in the treatment and the immune response to hepatocellular carcinoma: potential mechanisms.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that can affect or regulate a variety of cellular activities. The purpose of this study was to investigate therapeutic and immunologic effects of USP7 in hepatocellular carcinoma (HCC), and as well to evaluate potential mechanisms of action. USP7-related gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) dataset, International Cancer Genome Consortium (ICGC) dataset, and Gene Expression Omnibus (GEO) dataset. Pathways associated with USP7 were determined by gene set enrichment analysis (GSEA). The relationships among USP7, immunity, and drug therapy were also investigated and potential mechanisms of action were explored. TCGA database results demonstrated USP7 mRNA expression levels to be upregulated in HCC tissues. Results were validated with UALCAN, ICGC, and GSE10143 datasets, as well as immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) experiments and were consistent with TCGA database findings (all P<0.05). GSEA analysis demonstrated increased USP7 levels to be associated with CHEMOKINE, Janus kinase/signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase (MAPK), P53, vascular endothelial growth factor (VEGF), and wingless (WNT) signaling pathways. Based on immune correlation analysis, USP7 was dramatically associated with immune cells and immune checkpoint molecules. In terms of drug therapy, USP7 expression levels were significantly related to HCC sensitivity to ciclosporin, talazoparib, dabrafenib, trametinib, paclitaxel, sorafenib, bortezomib, sunitinib, and crizotinib. Based on these results, we mechanistically propose an association between USP7 and these four drug targets: B-Raf proto-oncogene serine/threonine protein kinase (BRAF), mitogen-activated extracellular signal-regulated kinase (MEK), DNA topoisomerase I (TOPOI), and poly ADP-ribose polymerase (PARP). USP7 plays a therapeutic and immunological role in HCC. The four drug targets BRAF, MEK, TOPOI, and PARP are implicated in the USP7 mechanism of action.

Identification and validation of a prognostic-related mutant gene DNAH5 for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide and has a poor prognosis. Thus, there is a need for an effective biomarker to improve and predict the prognosis of HCC. RNA sequencing data, simple nucleotide variation data, and clinical data of HCC patients from The Cancer Genome Atlas (TCGA) to identify mutant genes, simple nucleotide variation data, and clinical data of HCC patients from the International Cancer Genome Consortium (ICGC) to validate the prognostic value of mutant genes were the data sources of the present study. To identify the overall survival (OS)-related mutant genes, a Kaplan-Meier (KM) analysis was conducted. We carried out univariate Cox and multivariate Cox regression analyses to identify the independent prognostic factors. We also conducted a correlation analysis of immune cells and mutant genes. To explore the molecular mechanisms of mutant genes, we conducted a gene set enrichment analysis (GSEA). A nomogram was constructed to help predict the prognosis of HCC. In addition, we explored the expression profile of mutant genes in HCC based on a TCGA dataset, an ICGC dataset, and our own HCC tissue samples. We identified and validated a mutant gene, dynein axonemal heavy chain 5 (DNAH5), which was negatively related to the OS of HCC patients. Univariate Cox and multivariate Cox regression analyses revealed that the mutant gene DNAH5 could act as an independent prognostic factor for HCC. Most pathways of the mutant gene DNAH5 were involved in cancer development and progression based on GSEA analysis. The mutant gene DNAH5 was negatively correlated with monocytes, naive CD4 T cells, activated dendritic cells, and activated mast cells. In addition, the mRNA and protein levels of DNAH5 had a significantly higher level of expression in the tissue samples of patients with HCC. A nomogram consisting of the pathological stage, DNAH5, and tumor mutation burden (TMB) performed well. The mutant gene DNAH5 had a significantly higher level of expression in the tissue samples of patients with HCC, could act as an independent prognostic factor for HCC, and is a potential new immunotherapy target for HCC.

Novel immune-related gene signature for risk stratification and prognosis prediction in ovarian cancer

BackgroundThe immune system played a multifaceted role in ovarian cancer (OC) and was a significant mediator of ovarian carcinogenesis. Various immune cells and immune gene products played an integrated role in ovarian cancer (OC) progression, proved the significance of the immune microenvironment in prognosis. Therefore, we aimed to establish and validate an immune gene prognostic signature for OC patients’ prognosis prediction.MethodsDifferently expressed Immune-related genes (DEIRGs) were identified in 428 OC and 77 normal ovary tissue specimens from 9 independent GEO datasets. The Cancer Genome Atlas (TCGA) cohort was used as a training cohort, Univariate Cox analysis was used to identify prognostic DEIRGs in TCGA cohort. Then, an immune gene-based risk model for prognosis prediction was constructed using the LASSO regression analysis, and validated the accuracy and stability of the model in 374 and 93 OC patients in TCGA training cohort and International Cancer Genome Consortium (ICGC) validation cohort respectively. Finally, the correlation among risk score model, clinicopathological parameters, and immune cell infiltration were analyzed.ResultsFive DEIRGs were identified to establish the immune gene signature and divided OC patients into the low- and high-risk groups. In TCGA and ICGC datasets, patients in the low-risk group showed a substantially higher survival rate than high-risk group. Receiver operating characteristic (ROC) curves, t-distributed stochastic neighbor embedding (t-SNE) analysis and principal component analysis (PCA) showed the good performance of the risk model. Clinicopathological correlation analysis proved the risk score model could serve as an independent prognostic factor in 2 independent datasets.ConclusionsThe prognostic model based on immune-related genes can function as a superior prognostic indicator for OC patients, which could provide evidence for individualized treatment and clinical decision making.

Identification of positive cofactor 4 as a diagnostic and prognostic biomarker associated with immune infiltration in hepatocellular carcinoma

Background and aimsHuman positive cofactor 4 (PC4) is associated with the development and therapeutic resistance of several malignancies. However, the role of PC4 in hepatocellular carcinoma (HCC) remains obscure. MethodsThe expression status of PC4 was explored in Gene Expression Omnibus and The Cancer Genome Atlas datasets. Subsequently, the prognostic and diagnostic significance of PC4 in HCC patients was analyzed. Functional enrichment analyses were conducted to explore biological functions and potential mechanisms. The CIBERSORT algorithm was used for immune infiltration analysis. The risk signature was constructed by LASSO-Cox regression and was validated with the International Cancer Genome Consortium dataset. Quantitative real-time polymerase chain reaction was used to verify the expression levels of all genes. Tumor Immune Dysfunction and Exclusion analysis evaluated immunotherapy response. Finally, using online databases, PC4-related competing endogenous RNA networks were constructed. ResultsPC4 levels were significantly upregulated in HCC and positively correlated with the pathological grade and clinical stage. The PC4-high expression group showed worse prognosis. In addition, PC4 could distinguish between tumor and normal tissues with an area under the curve of 0.965. The PC4 level was associated with immune checkpoints and immune cell infiltration. In the training and validation sets, the eight-gene risk signature strongly correlated with HCC patient prognosis. Tumor Immune Dysfunction and Exclusion analysis showed that patients in both the PC4-low and low-risk groups were more likely to benefit from immunotherapy. Finally, an lncRNA/microRNA-101-3p/PC4 network was constructed. ConclusionWe confirmed PC4 as a diagnostic and prognostic biomarker in HCC patients. We also developed and validated an eight-gene risk signature, which will help in clinical decision-making. The competing endogenous RNA network could help explore the regulatory mechanisms of PC4 in HCC.

Cuproptosis-related prognostic signatures predict the prognosis and immunotherapy in HCC patients.

Cuproptosis, an unusual type of programmed cell death mechanism of cell death, involved the disruption of specific mitochondrial metabolic enzymes in the occurrence and development of tumors. However, it was still unclear how the relationship between cuproptosis-related genes (CRGs) may contribute to hepatocellular carcinoma (HCC) potential the prognosis of HCC remained limited. Here, the landscape of 14 CRGs in HCC was evaluated using the Cancer Genome Atlas and International Cancer Genome Consortium datasets. And then, 4 CRGs (ATP7A, MTF1, GLS, and CDKN2A) were screened for the construction of risk signatures for prognosis and drug therapy. The HCC patients with CRGs high-risk showed poor prognosis than those with low risk. Moreover, the CRGs risk signature was shown to be an independent prognostic factor and associated with the immune microenvironment in HCC. Meanwhile, we constructed and verified a prognostic model based on cuproptosis-related lncRNAs (Cr-lncRNAs). We obtained 291 Cr-lncRNAs and constructed Cr-lncRNA prognosis signature based on 3 key Cr-lncRNAs (AC026356.1, NRAV, AL031985.3). The Cr-lncRNA prognosis signature was also an independent prognostic factor and associated with the immune microenvironment in HCC. Finally, the drug sensitivity database showed that 8 candidate drugs related to CRGs signature and Cr-lncRNAs signature. In summary, we evaluated and validated the CRGs and Cr-lncRNAs as potential predictive markers for prognosis, immunotherapy, and drug candidate with the personalized diagnosis and treatment of HCC.

Prognostic and Immunological Significance of the Molecular Subtypes and Risk Signatures Based on Cuproptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains a challenging medical problem. Cuproptosis is a novel form of cell death that plays a crucial role in tumorigenesis, angiogenesis, and metastasis. However, it remains unclear whether cuproptosis-related genes (CRGs) influence the outcomes and immune microenvironment of HCC patients. From The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we obtained the mRNA expression file and related clinical information of HCC patients. We selected 19 CRGs as candidate genes for this study according to previous literature. We performed a differential expression analysis of the 19 CRGs between malignant and precancerous tissue. Based on the 19 CRGs, we enrolled cluster analysis to identify cuproptosis-related subtypes of HCC patients. A prognostic risk signature was created utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. We employed independent and stratification survival analyses to investigate the predictive value of this model. The functional enrichment features, mutation signatures, immune profile, and response to immunotherapy of HCC patients were also investigated according to the two molecular subtypes and the prognostic signature. We found that 17 CRGs significantly differed in HCC versus normal samples. Cluster analysis showed two distinct molecular subtypes of cuproptosis. Cluster 1 is preferentially related to poor prognosis, high activity of immune response signaling, high mutant frequency of TP53, and distinct immune cell infiltration versus cluster 2. Through univariate and LASSO Cox regression analyses, we created a cuproptosis-related prognostic risk signature containing LIPT1, DLAT, MTF1, GLS, and CDKN2A. High-risk HCC patients were shown to have a worse prognosis. The risk signature was proved to be an independent predictor of prognosis in both the TCGA and ICGC datasets, according to multivariate analysis. The signature also performed well in different stratification of clinical features. The immune cells, which included regulatory T cells (Treg), B cells, macrophages, mast cells, NK cells, and aDCs, as well as immune functions containing cytolytic activity, MHC class I, and type II IFN response, were remarkably distinct between the high-risk and low-risk groups. The tumor immune dysfunction and exclusion (TIDE) score suggested that high-risk patients had a higher response rate to immune checkpoint inhibitors than low-risk patients. This research discovered the potential prognostic and immunological significance of cuproptosis in HCC, improved the understanding of cuproptosis, and may deliver new directions for developing more efficacious therapeutic techniques for HCC patients.

Identification of fatty acid metabolism-related clusters and immune infiltration features in hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is a type of liver cancer which is characterized by inflammation-associated tumor. The unique characteristics of tumor immune microenvironment in HCC contribute to hepatocarcinogenesis. It was also clarified that aberrant fatty acid metabolism (FAM) might accelerate tumor growth and metastasis of HCC. In this study, we aimed to identify fatty acid metabolism-related clusters and establish a novel prognostic risk model in HCC. Gene expression and corresponding clinical data were searched from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) portal. From the TCGA database, by unsupervised clustering method, we determined three FAM clusters and two gene clusters with distinct clinicopathological and immune characteristics. Based on 79 prognostic genes identified from 190 differentially expressed genes (DEGs) among three FAM clusters, five prognostic DEGs (CCDC112, TRNP1, CFL1, CYB5D2, and SLC22A1) were determined to construct risk model by least absolute shrinkage and selection operator (LASSO) and multivariate cox regression analysis. Furthermore, the ICGC dataset was used to validate the model. In conclusion, the prognostic risk model constructed in this study exhibited excellent indicator performance of overall survival, clinical feature, and immune cell infiltration, which has the potential to be an effective biomarker for HCC immunotherapy.

Identification of Anoikis-Related Subgroups and Prognosis Model in Liver Hepatocellular Carcinoma.

Resistance to anoikis is a key characteristic of many cancer cells, promoting cell survival. However, the mechanism of anoikis in hepatocellular carcinoma (HCC) remains unknown. In this study, we applied differentially expressed overlapping anoikis-related genes to classify The Cancer Genome Atlas (TCGA) samples using an unsupervised cluster algorithm. Then, we employed weighted gene coexpression network analysis (WGCNA) to identify highly correlated genes and constructed a prognostic risk model based on univariate Cox proportional hazards regression. This model was validated using external datasets from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Finally, we used a CIBERSORT algorithm to investigate the correlation between risk score and immune infiltration. Our results showed that the TCGA cohorts could be divided into two subgroups, with subgroup A having a lower survival probability. Five genes (BAK1, SPP1, BSG, PBK and DAP3) were identified as anoikis-related prognostic genes. Moreover, the prognostic risk model effectively predicted overall survival, which was validated using ICGC and GEO datasets. In addition, there was a strong correlation between infiltrating immune cells and prognostic genes and risk score. In conclusion, we identified anoikis-related subgroups and prognostic genes in HCC, which could be significant for understanding the molecular mechanisms and treatment of HCC.

A Novel Gene Signature Associated with Inflammatory Responses and Immune Status Assists in Prognosis and Intervention for Patients with HCC.

Tumor growth depends on tumor cells and the tumor microenvironment, which are regulated by inflammation and immune responses. However, the roles of inflammation and immune status in hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to evaluate the prognostic value of an inflammatory response- related gene signature associated with immune status, which may provide insight into new treatment options for HCC patients. Differentially expressed genes associated with inflammation were obtained from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus, and the Molecular Signatures Database. An inflammation-associated prognostic gene signature was constructed and validated using TCGA and the International Cancer Genome Consortium datasets, respectively, using LASSO Cox regression analysis. Log-rank was performed to compare the overall survival of low- and high-risk score cohorts. Immune cell infiltration and immune-related functions were analyzed using single-sample gene enrichment analysis. The structures of the drugs identified by the prognostic model were predicted using PubChem. The drugs sensitivity of bleomycin, simvastatin and zoledronate detected by CCK8 colorimetric assay. The mRNA levels of 7 genes in HCC after drug treatment analyzed via qRT-PCR. Inflammation-associated genes, including ITGA5, MEP1A, P2RX4, RIPK2, SLC7A1 and SRI, were identified and found to be associated with the prognosis of HCC. We further found that the high-risk patients experienced poor prognosis, which was observed to be an independent and significant risk factor for prognosis. Moreover, we observed elevated expression levels in multiple immune cell types and immune function. Lastly, we validated that bleomycin, simvastatin and zoledronate could regulate these genes in HCC. The inflammatory-response-associated gene signature could predict the prognosis and the immunological status of HCC patients. Additionally, bleomycin, simvastatin and zoledronate may represent potential drug candidates that could inhibit these genes. This may constitute a new approach for the treatment of HCC.

A novel risk score based on immune-related genes for hepatocellular carcinoma as a reliable prognostic biomarker and correlated with immune infiltration.

Immunological-related genes (IRGs) play a critical role in the immune microenvironment of tumors. Our study aimed to develop an IRG-based survival prediction model for hepatocellular carcinoma (HCC) patients and to investigate the impact of IRGs on the immune microenvironment. Differentially expressed IRGs were obtained from The Genomic Data Commons Data Portal (TCGA) and the immunology database and analysis portal (ImmPort). The univariate Cox regression was used to identify the IRGs linked to overall survival (OS), and a Lasso-regularized Cox proportional hazard model was constructed. The International Cancer Genome Consortium (ICGC) database was used to verify the prediction model. ESTIMATE and CIBERSORT were used to estimate immune cell infiltration in the tumor immune microenvironment (TIME). RNA sequencing was performed on HCC tissue specimens to confirm mRNA expression. A total of 401 differentially expressed IRGs were identified, and 63 IRGs were found related to OS on the 237 up-regulated IRGs by univariate Cox regression analyses. Finally, five IRGs were selected by the LASSO Cox model, including SPP1, BIRC5, STC2, GLP1R, and RAET1E. This prognostic model demonstrated satisfactory predictive value in the ICGC dataset. The risk score was an independent predictive predictor for OS in HCC patients. Immune-related analysis showed that the immune infiltration level in the high-risk group was higher, suggesting that the 5-IRG signature may play an important role in mediating immune escape and immune resistance in the TIME of HCC. Finally, we confirmed the 5-IRG signature is highly expressed in 65 HCC patients with good predictive power. We established and verified a new prognosis model for HCC patients based on survival-related IRGs, and the signature could provide new insights into the prognosis of HCC.

Risk Predictive Model Based on Three DDR-Related Genes for Predicting Prognosis, Therapeutic Sensitivity, and Tumor Microenvironment in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the second most common cause of cancer-related deaths. Tumor mutational load, genomic instability, and tumor-infiltrating lymphocytes were associated with DNA damage response and repair gene changes. The goal of this study is to estimate the chances of patients with HCC surviving their disease by constructing a DNA damage repair- (DDR-) related gene profile. The International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) provided us with the mRNA expression matrix as well as clinical information relevant to HCC patients. Using Cox regression and LASSO analysis, DEGs strongly related to general survival were discovered in the differentially expressed gene (DEG) study. In order to assess the model's accuracy, Kaplan-Meier (KM) and receiver operating characteristic (ROC) were used. In order to compute the immune cell infiltration score and immune associated pathway activity, a single-sample gene set enrichment analysis was performed. A three-gene signature (CDC20, TTK, and CENPA) was created using stability selection and LASSO COX regression. In comparison to the low-risk group, the prognosis for the high-risk group was surprisingly poor. In the ICGC datasets, the predictive characteristic was confirmed. A receiver operating characteristic (ROC) curve was calculated for each cohort. The risk mark for HCC patients is a reliable predictor according to multivariate Cox regression analysis. According to ssGSEA, this signature was highly correlated with the immunological state of HCC patients. There was a significant correlation between the expression levels of prognostic genes and cancer cells' susceptibility to antitumor therapies. Overall, a distinct gene profile associated with DDR was identified, and this pattern may be able to predict HCC patients' long-term survival, immune milieu, and chemotherapeutic response.

The Prognostic Value of Lysine Acetylation Regulators in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a tumor with high morbidity and mortality worldwide. lysine acetylation regulators (LARs) dynamically regulate Lysine acetylation modification which plays an important regulatory role in cancer. Therefore, we aimed to explore the potential clinical prognostic value of LARs in HCC. Methods: Differentially expressed LARs in normal liver and HCC tissues were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. To identify genes with prognostic value and establish the risk characteristics of LARs, consensus clustering was employed. We used univariate Cox regression survival analysis and LASSO Cox regression based on LARs to determine the independent prognostic signature of HCC. CIBERSORT and Gene Set Enrichment Analysis (GSEA) were used to estimate immune infiltration and functional enrichment analysis respectively. The expression of LAR was detected by Real-time quantitative polymerase chain reaction (RT-qPCR). statistical analyses were conducted using SPSS and R software. Results: In this study, the 33 LARs expression data and corresponding clinical information of HCC were obtained using TCGA and ICGC datasets. We found majority of the LARs were differentially expressed. Consensus cluster analysis was carried out based on the TCGA cohort, and three HCC subtypes (cluster 1, 2, and 3) were obtained. The LA3 subgroup had the worst clinical outcomes. Nine key LARs were identified to affect prognosis. The results showed that LARs signature has a strong independent prognostic value in HCC patients, whether in the training datasets or in the testing datasets. GSEA results showed that various tumor-related processes and pathways were abundant in the high-risk groups. RT-qPCR results showed that HAT1, HDAC1, HDAC2, HDAC4, and HDAC11 were highly expressed in HCC cells. Conclusion: Our results suggest that LARs play critical roles in HCC and are helpful for individual prognosis monitoring and clinical decision-making of HCC.

LRP1B is a Potential Biomarker for Tumor Immunogenicity and Prognosis of HCC Patients Receiving ICI Treatment.

BackgroundNew predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown.MethodsThe most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC.ResultsLRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues.ConclusionThis study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.

Ferroptosis-Related IncRNAs Are Prognostic Biomarker of Overall Survival in Pancreatic Cancer Patients.

Pancreatic cancer (PC) is one of the most lethal malignancies, the mortality and morbidity of which have been increasing over the past decade. Ferroptosis, a newly identified iron-dependent cell death pattern, can be induced by iron chelators and small lipophilic antioxidants. Nonetheless, the prognostic significance of ferroptosis-related lncRNAs in PC remains to be clarified. We obtained the lncRNA expression matrix and clinicopathological information of PC patients from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets in the current study. Firstly, we conducted Pearson correlation analysis to delve into the ferroptosis-related lncRNAs, and univariate Cox analysis was implemented to examine the prognostic values in PC patients. Twenty-three prognostic ferroptosis-related lncRNAs were confirmed and loaded into the least absolute shrinkage and selection operator Cox (LASSO-Cox) analysis, then a ferroptosis-related lncRNA prognostic marker (Fe-LPM) was established in the TCGA dataset. Risk scores of patients were calculated and segregated PC patients into low-risk and high-risk subgroups in each dataset. The prognostic capability of Fe-LPM was also confirmed in the ICGC dataset. Gene set enrichment analysis (GSEA) revealed that several ferroptosis-related pathways were enriched in low-risk subgroups. Furthermore, we adopted a multivariate Cox regression to establish a nomogram based on risk score, age, pathological T stage and primary therapy outcome. A competing endogenous RNA (ceRNA) network was also created relied on four of the twenty-three ferroptosis-related lncRNAs. In conclusion, the eight Fe-LPM can be utilized to anticipate the overall survival (OS) of PC patients, which are meaningful to guiding clinical strategies in PC.

Survival Prognosis, Tumor Immune Landscape, and Immune Responses of PPP1R18 in Kidney Renal Clear Cell Carcinoma and Its Potentially Double Mechanisms.

BackgroundThe aim of this study was to investigate the immunological and prognostic roles of protein phosphatase 1 regulatory subunit 18 (PPP1R18) for overall survival (OS) in kidney renal clear cell carcinoma (KIRC) patients, as well as the prediction of its potential mechanisms.MethodsBased on PPP1R18 single gene expression matrices and clinical information from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and GSE6344 datasets, the relationships between PPP1R18 and prognosis/immunity were fully explored. Univariate and multivariate Cox regression analyses were applied to assess its independent prognostic ability and gene set enrichment analysis (GSEA) was implemented to find its related pathways. Besides, we also explored possible mechanisms of PPP1R18 involved in KIRC.ResultsPPP1R18 was highly expressed in KIRC samples than in non-tumor tissues in TCGA, ICGC and GSE6344 datasets, with validations from quantitative real-time polymerase chain reaction (qRT-PCR) in both cell lines and KIRC tissues (all P < 0.05). Univariate and multivariate Cox regression analyses indicated that PPP1R18 was also considered to be with independent prognostic ability in KIRC (both P < 0.01). GSEA results showed that PPP1R18 gene expression was significantly related to Chemokine, JAK STAT, MAPK, and NOTCH pathways. Furthermore, PPP1R18 was also firmly associated with microsatellite instability (MSI), tumor mutational burden (TMB), immune microenvironment, immune cells, immune checkpoints and immune infiltration (all P < 0.05). Analysis of tumor immune dysfunction and exclusion (TIDE) and Imvigor210 datasets suggested that patients with low PPP1R18 expression are more likely to benefit from immunotherapy. Finally, we identified two potential mechanisms of a classical competing endogenous RNA (ceRNA) mechanism and an RNA-binding protein (RBP) involved mechanism of PPP1R18 in KIRC.ConclusionsPPP1R18 played oncogenic and immunological roles of OS in KIRC, offering potential antigens for developing KIRC mRNA vaccines.

High Expression of CHST11 Correlates with Poor Prognosis and Tumor Immune Infiltration of Pancreatic Cancer.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and its prognosis is poor. It has been reported that carbohydrate sulfotransferase 11 (CHST11) is associated with tumor progression in various cancers but rarely reported in PC. The aim of this study was to comprehensively investigate the clinical value of CHST11 in PC. CHST11 gene expression analysis was conducted by The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA) databases. Survival analysis and receiver operating characteristic (ROC) curves were performed to evaluate the prognostic significance of CHST11 based on TCGA and International Cancer Genome Consortium (ICGC) databases. Additionally, functional enrichment analysis was also performed. Moreover, single-sample Gene Set Enrichment Analysis (ssGSEA) and ESTIMATE algorithm were used to assess immune infiltration. Finally, the relationship between CHST11 expression and immune checkpoint gene levels was estimated by Spearman's correlation analysis. CHST11 was highly expressed in PC tissues compared with normal tissues, and the expression of CHST11 was related to T stage, N stage, and histological grade. The survival time of PC patients with CHST11 low-expression was significantly better than those with CHST11 high-expression. The areas under the ROC curve corresponding to 1-, 3-, and 5-year survival in the TCGA dataset were 0.573, 0.671, and 0.740, respectively, and those in the ICGC dataset were 0.588, 0.602, and 0.626, respectively. Functional enrichment analysis showed that CHST11 may be involved in the regulation of immune function. Finally, the level of CHST11 was significantly correlated with 22 types of tumor-infiltrating immune cells, immune and stromal scores, and 7 immune checkpoint genes. High-expression of CHST11 was correlated with poor prognosis and tumor immune infiltration in PC. Moreover, CHST11 may act as a novel prognostic marker and potential therapeutic target of PC.

Bioinformatic Analysis of Immune Significance of RYR2 Mutation in Breast Cancer.

Background Currently, immunotherapy is widely used for breast cancer (BC) patients, and tumor mutation burden (TMB) is regarded as a valuable independent predictor of response to immunotherapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immune cells in BC are not fully understood. Methods Comprehensive bioinformatic analyses were performed using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Survival curves were analyzed via Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were used for prognosis analysis. Gene set enrichment analysis (GSEA) was performed to explore regulatory mechanisms and functions. The CIBERSORT algorithm was used to calculate the tumor-infiltrating immune cell fractions. Results We analyzed somatic mutation data of BC from TCGA and ICGC datasets and found that 19 frequently mutated genes were reported in both cohorts, namely, SPTA1, TTN, MUC17, MAP3K1, CDH1, FAT3, SYNE1, FLG, HMCN1, RYR2 (ryanodine receptor 2), GATA3, MUC4, PIK3CA, KMT2C, TP53, PTEN, ZFHX4, MUC16, and USH2A. Among them, we observed that RYR2 mutation was significantly associated with higher TMB and better clinical prognosis. Moreover, GSEA revealed that RYR2 mutation-enriched signaling pathways were related to immune-associated pathways. Furthermore, based on the CIBERSORT algorithm, we found that RYR2 mutation enhanced the antitumor immune response by enriching CD8+ T cells, activated memory CD4+ T cells, and M1 macrophages. Conclusion RYR2 is frequently mutated in BC, and its mutation is related to increased TMB and promotes antitumor immunity; thus, RYR2 may serve as a valuable biomarker to predict the immune response.

Titin Mutation Is Associated With Tumor Mutation Burden and Promotes Antitumor Immunity in Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSC) is a leading cause of mobidity and mortality worldwide. Recently, there was a shift in the treatment pattern of immune therapy in LUSC patients; merely a small number of patients with non-small cell lung cancer (NSCLC) at advanced stages respond well to immune checkpoint blockade (ICB) therapy, and tumor mutation burden (TMB) is a valuable independent indicator of response to immune therapy. However, specific gene mutations and their relationship with TMB and tumor-infiltrating immunocytes in LUSC are still unclear. In the present paper, our team analyzed the somatically mutated genes from the ICGC (International Cancer Genome Consortium) and TCGA (The Cancer Genome Atlas) datasets and discovered that 15 frequent gene mutations occurred in both cohorts, including ZFHX4, MUC16, FLG, TP53, LRP1B, TTN, SYNE1, RYR2, CSMD3, USH2A, MUC17, DNAH5, FAM135B, COL11A1, and RYR3. Interestingly, only mutated TTN was related to higher TMB and prognostic outcomes among the 15 mutated genes. Moreover, according to the CIBERSORT algorithm, we revealed that TTN mutation enhanced the antitumor immune response. In conclusion, TTN may have important clinical implications for relevant immune therapy of lung squamous carcinoma.