Pan-Cancer Pyroptosis Analyses Identified Novel Immunology and Chemotherapy-Related Prognostic Signatures in Cancer Subtypes.
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ABSTRACT:
SUBMITTER: Li C
PROVIDER: S-EPMC9236821 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCancer cells become immortalized through telomere maintenance mechanisms, such as telomerase reverse transcriptase (TERT) activation. In addition to maintaining telomere length, TERT activates manifold cell survival signaling pathways. However, telomerase-associated gene signatures in cancer remain elusive.MethodsWe performed a systematic analysis of TERT high (TERThigh) and low (TERTlow) cancers using multidimensional data from The Cancer Genome Atlas (TCGA). Multidimensional data were analyzed by propensity score matching weight algorithm. Coexpression networks were constructed by weight gene coexpression network analysis (WGCNA). Random forest classifiers were generated to identify cancer subtypes.ResultsThe TERThigh-specific mRNA expression signature is associated with cell cycle-related coexpression modules across cancer types. Experimental screening of hub genes in the cell cycle module suggested TPX2 and EXO1 as potential regulators of telomerase activity and cell survival. MiRNA analysis revealed that the TERThigh-specific miR-17-92 cluster can target biological processes enriched in TERTlow cancer and that its expression is negatively correlated with the tumor/normal telomere length ratio. Intriguingly, TERThigh cancers tend to have mutations in extracellular matrix organization genes and amplify MAPK signaling. By mining the clinical actionable gene database, we uncovered a number of TERThigh-specific somatic mutations, amplifications and high expression genes containing therapeutic targets. Finally, a random forest classifier integrating telomerase-associated multi-omics signatures identifies two cancer subtypes showed profound differences in telomerase activity and patient survival.ConclusionsIn summary, our results depict a telomerase-associated molecular landscape in cancers and provide therapeutic opportunities for cancer treatment.
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Project description:BackgroundBladder carcinoma (BLCA) is a common malignant tumor with high morbidity and mortality in the urinary system. Pyroptosis is a pattern of programmed cell death that is closely associated with progression of tumors. Therefore, it is significant to probe the expression of pyroptosis-related genes (PRGs) in BLCA.MethodsThe differentially expressed genes in normal and BLCA tissues were first obtained from the Cancer Genome Atlas (TCGA) database analysis, as well as PRGs from the National Center for Biotechnology Information (NCBI) database, intersecting to obtain differentially expressed pyroptosis-related genes (DEPRGs) in BLCA. With the construction of a prognostic model of pyroptosis by regression analysis, we derived and validated key genes, which were ascertained as a separate prognostic marker by individual prognostic and clinical relevance analysis. In addition, we gained six immune cells from the Tumor Immune Evaluation Resource (TIMER) website and analyzed the relationship between pyroptosis prognostic genes and immune infiltration.ResultOur results revealed that 31 DEPRGs were available by comparing normal and BLCA tissues with |log2 (fold change, FC)| > 0.5 and FDR <0.05. Four key genes (CRTAC1, GSDMB, AIM2, and FOXO3) derived from the pyroptosis prognostic model were experimentally validated for consistent expression in BLCA patients. Following risk scoring, the low-risk group of BLCA patients had noticeably higher overall survival (OS) than the high-risk group (p < 0.001). Risk score was still an independent prognostic factor (HR = 1.728, 95% CI =1.289-2.315, p < 0.001). In addition, we found remarkable correlations among the expression of pyroptosis-related prognostic genes and the immune infiltration of CD4+ T cells, CD8+ T cells, B cells, dendritic cells, macrophages, and neutrophils.ConclusionGenes (CRTAC1, GSDMB, AIM2, and FOXO3) associated with pyroptosis are potential BLCA prognostic biomarkers that act as an essential part in the predictive prognosis of survival and immunotherapy of BLCA.
| S-EPMC9280833 | biostudies-literature
Project description:BackgroundProgrammed cell death is an active and orderly form of cell death regulated by intracellular genes that plays an important role in the normal occurrence and development of the immune system, and pyroptosis has been found to be involved in tumorigenesis and development. However, compressive analysis and biological regulation of pyroptosis genes are lacking in cancers.MethodsUsing data from The Cancer Genome Atlas, we established a score level model to quantify the pyroptosis level in cancer. Multiomics bioinformatic analyses were performed to assess pyroptosis-related molecular features and the effect of pyroptosis on immunotherapy in cancer.ResultsIn the present study, we performed a comprehensive analysis of pyroptosis and its regulator genes in cancers. Most pyroptosis genes were aberrantly expressed in different types of cancer, attributed to the CAN frequency and differences in DNA methylation levels. We established a pyroptosis level model and found that pyroptosis had dual roles across cancers, while the pyroptosis levels were different among multiple cancers and were significantly associated with clinical prognosis. The dual role of pyroptosis was also shown to affect immunotherapeutic efficacy in several cancers. Multiple pyroptosis genes showed close associations with drug sensitivity across cancers and may be considered therapeutic targets in cancer.ConclusionsOur comprehensive analyses provide new insight into the functions of pyroptosis in the initiation, development, progression and treatment of cancers, suggesting corresponding prognostic and therapeutic utility.
| S-EPMC8896277 | biostudies-literature
Project description:Pyroptosis is a newly characterized type of programmed cell death. However, its function in cancer progression and its response to treatments remain controversial. Here, we extensively and systematically compiled genes associated with pyroptosis, integrated multiomics data and clinical data across 31 cancer types from The Cancer Genome Atlas, and delineated the global alterations in PRGs at the transcriptional level. The underlying transcriptional regulations by copy number variation, miRNAs, and enhancers were elucidated by integrating data from the Genotype-Tissue Expression and International Cancer Genome Consortium. A prognostic risk model, based on the expression of PRGs across 31 cancer types, was constructed. To investigate the role of pyroptosis in immunotherapy, we found five PRGs associated with effectiveness by exploring the RNA-Seq data of patients with immunotherapy, and further identified two small-molecule compounds that are potentially beneficial for immunotherapy. For the first time, from a pyroptosis standpoint, this study establishes a novel strategy to predict cancer patient survival and immunotherapeutic outcomes.
| S-EPMC8750048 | biostudies-literature
Project description:Increasing evidence has clarified that the tumor microenvironment (TME) is closely related to the prognosis and therapeutic efficacy of cancer. However, there is no reliable TME evaluation system used to accurately predict the prognosis of and therapeutic efficacy in gastric cancer. We evaluated the immune microenvironment score (IMS) of 1422 gastric cancer samples based on 51 immune cell signatures. We explored the relationship between the IMS and prognosis, immune cell infiltration, cancer subtype, and potential immune escape mechanisms. The results show that activation of the stroma and decreased levels of immune infiltration were associated with a low IMS. A high IMS was characterized by Epstein-Barr virus infection, increased mutation load, microsatellite instability, and immune cell infiltration. A high IMS was also related to high expression of immune checkpoint molecules (PD-1/PD-L1). Finally, patients with a high IMS had a better response to PD-1/PD-L1 inhibitors and may be more suitable for immune checkpoint inhibitors (area under the curve = 0.81). In addition, a low IMS may be converted into the immune-infiltrating subtype after romidepsin treatment. Stratification based on the IMS may enable gastric cancer patients to benefit more from immunotherapy and help identify new cancer treatment strategies.
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Project description:Background: IGSF10 is a member of the immunoglobulin superfamily. Over the previous decade, growing proof has validated definitive correlations between individuals of the immunoglobulin superfamily and human diseases. However, the function of IGSF10 in pan-cancer stays unclear. We aimed to analyze the immunological and prognostic value of IGSF10 in pan-cancer. Methods: We utilized a vary of bioinformatic ways to inspect the function of IGSF10 in pan-cancer, including its correlation with prognosis, immune cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferases, genetic alteration, drug sensitivity, etc. Results: We noticed low expression of IGSF10 in most cancer types. IGSF10 expression in tumor samples correlates with prognosis in most cancers. In most cancer types, IGSF10 expression was strongly related to immune cells infiltration, immune checkpoints, immune modulators, TMB, MSI, MMR, and DNA methyltransferases, among others. Functional enrichment analyses indicated that IGSF10 expression was involved in lymphocyte differentiation, cell molecules adhesion, etc. Furthermore, low IGSF10 expression could increase the drug sensitivity of many drugs. Conclusion: IGSF10 could serve as a novel prognostic marker and attainable immunotherapy target for several malignancies.
| S-EPMC9845414 | biostudies-literature
Project description:BackgroundOsteomimicry of cancer cells had been widely reported in prostate cancer and breast cancer. However, the prognostic value of osteomimicry in various cancer types remained unclear. We hypothesized that osteomimicry would result in remodeling of the tumor microenvironment and was eligible to predict patient prognosis.MethodsA comprehensive transcriptomic analysis of the osteomimicry, which was characterized by mRNA expression of SPARC, SPP1, and BGLAP, across 20 solid tumors (7564 patients) using RNA-seq data from The Cancer Genome Atlas (TCGA) was conducted. Samples of each cancer type were classified into subgroups (high vs. low) based on median value of osteomimetic markers, the associations of these markers with clinical outcomes, immune cell infiltration and immune checkpoints expression were explored.ResultsEach osteomimetic marker harbored prognostic value in the pan-cancer analyses [SPARC: hazard ratio (HR) = 1.10, p = 0.028; SPP1: HR = 1.25, p < 0.001; BGLAP: HR = 1.13, p = 0.005]. Patients with high expression of all the three genes also had significantly unfavorable survival (HR = 1.61, p < 0.0001) compared with those of low expression. Correlation analyses demonstrated that osteomimicry was closely related to tumor purity, dendritic cells (DC) infiltration and expression of immune checkpoints.ConclusionOsteomimicry had prognostic value in various cancer types and the underlying mechanism might correlate to the trapping and dysfunction of DCs in the tumor microenvironment, revealing the potential of osteomimicry as a target of immunotherapy.
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Project description:Background IQGAP3 has important function in cancer progression and has become a potential therapeutic target as a transmembrane protein. But its role in tumor immunity and pan-cancer was not systematically investigated. This study evaluated the potential role of IQGAP3 and clinical significance in pan-cancer through combined multiomics analysis. Methods From Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, transcriptomic datasets were first obtained, and from Gene Expression Omnibus (GEO), expression profiling microarray data were acquired and integrated to systematically assess the expression differences and prognostic relevance of IQGAP3 in pancreatic cancer. Immunohistochemical data were obtained from Human Protein Atlas (HPA) to assess IQGAP3 protein expression differences, and exome data from TCGA were used to analyze IQGAP3 expression in relation to tumor mutational burden (TMB), microsatellite instability (MSI), and mutation. Additionally, we also analyzed the relationship between IQGAP3 expression and immune checkpoints, mismatch repair (MMR), and IQGAP3 relationship with methylation and copy number variation based on expression profiles. Results Microsatellite instability (MSI), immune checkpoints, mismatch repair (MMR), and tumor mutational burden (TMB) all closely interacted with IQGAP3 mRNA. In addition, detailed relationships between the immune microenvironment and IQGAP3 mRNA as well as immune cell CD4+ Th2 and myeloid-derived suppressor cells (MDSCs) were determined. Mechanistically, IQGAP3 was involved in cytoskeleton formation, T cell receptor signaling pathways, DNA damage, cell cycle, P53 pathway, Fc gamma R-mediated phagocytosis, and apoptosis. Conclusion IQGAP3 could serve as an effective prognostic biomarker for pan-cancer immune-related therapy.
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Project description:The important role of pyroptosis in tumor progression has been well characterized in recent years. However, little is known about the impact of tumor pyroptosis characteristics on patient prognosis and tumor microenvironment (TME) as well as efficacy of immunotherapy. In this study, we successfully classified colon cancer samples into three pyroptosis characterizations with different prognosis and TME cell infiltration patterns based on the expression of pyroptosis-related genes. Cluster 2, with the characterizations of immunosuppression, was classified as immune-desert cell infiltration patterns. Cluster 3, with the patterns of immune-inflamed cell infiltration, had the feature of an activated innate and adaptive immunity and significant prolonged survival. The activation of stromal pathways including EMT, angiogenesis and TGF-β in cluster 1 may mediate the impaired immune penetration of this cluster, which was classified as immune-excluded cell infiltration patterns. Our results demonstrated the PyroSig signature was a robust and independent biomarker for predicting patient prognosis. Patients with low PyroSig signature was confirmed to be correlated with treatment advantages and significant prolonged survival in two anti-checkpoint immunotherapy cohorts. This study identified three pyroptosis-related subtypes with distinct molecular features, clinical and microenvironment cell infiltration patterns in colon cancer, which could promote individualized immunotherapy for colon cancer.
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Project description:Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2) is a two-domain transmembrane protein-coding gene located on chromosome 3, the protein expressed by which acts as the membrane receptor of semaphorin and vascular endothelial growth factor during the development of axons and blood vessels. Although several research evidences at the cellular and clinical levels have associated DCBLD2 with tumorigenesis, nothing is known regarding this gene from a pan-cancer standpoint. In this study, we systematically analyzed the influence of DCBLD2 on prognosis, cancer staging, immune characteristics, and drug sensitivity in a variety of cancers based on a unified and standardized pan-cancer dataset. In addition, we performed GO enrichment analyses and KEGG analyses of DCBLD2-related genes and DCBLD2-binding proteins. Our results showed that DCBLD2 is a potential oncogenic, immunological as well as a prognostic biomarker in terms of pan-cancer, and is expected to contribute to the improvement of tumor prognosis and the development of targeted therapy.
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