Abstract
Integrative analysis was performed in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas to describe the pyroptosis-associated molecular classification and prognostic signature in glioma. Pyroptosis-related genes were used for consensus clustering and to develop a prognostic signature. The immune statuses, molecular alterations, and clinical features of differentially expressed genes were analyzed among different subclasses and risk groups. A lncRNA-miRNA-mRNA network was built, and drug sensitivity analysis was used to identify small molecular drugs for the identified genes. Glioma can be divided into two subclasses using 30 pyroptosis-related genes. Cluster 1 displayed high immune signatures and poor prognosis as well as high immune-related function scores. A prognostic signature based on 15 pyroptosis-related genes of the CGGA cohort can predict the overall survival of glioma and was well validated in the TCGA cohort. Cluster 1 had higher risk scores. The high-risk group had high immune cell and function scores and low DNA methylation of pyroptosis-related genes. The differences in pyroptosis-related gene mutations and somatic copy numbers were significant between the high-risk and low-risk groups. The ceRNA regulatory network uncovered the regulatory patterns of different risk groups in glioma. Nine pairs of target genes and drugs were identified. In vitro, CASP8 promotes the progression of glioma cells. Pyroptosis-related genes can reflect the molecular biological and clinical features of glioma subclasses. The established prognostic signature can predict prognosis and distinguish molecular alterations in glioma patients. Our comprehensive analyses provide valuable guidelines for improving glioma patient management and individualized therapy.
Highlights
Gliomas are the most common types of primary tumors in the central nervous system and one of the most devastating tumors (Weller et al, 2015)
In the coupling of the amino-terminal and carboxy-terminal linkers of gasdermin D (GSDMD) by caspases, the latter is displaced onto the membrane and perforated, inducing moisture penetration, cell swelling and the release of inflammatory factors, which is followed by pyroptosis (Boise and Collins, 2001)
We first explored the interactions among these genes using PPIs (Figure 1B), and the PPI network indicated that CASP8, CASP4, CASP1, NLRP3, NLRP1, and nucleotide-binding oligomerization domain-like receptor protein C4 (NLRC4) are hub genes
Summary
Gliomas are the most common types of primary tumors in the central nervous system and one of the most devastating tumors (Weller et al, 2015). The exploration and research of the underlying mechanism of gliomas and identification of potential treatment targets followed by application in clinical practice have important theoretical and practical significance. Pyroptosis is one of the pathways involved in programmed cell death, such as apoptosis, ferroptosis, necroptosis, and autophagy (Fink and Cookson, 2005). Cookson et al first used pyroptosis to describe the caspase-1-dependent pattern of cell death found in macrophages (Fink and Cookson, 2006). Pyroptosis, distinct from apoptosis and necrosis, contributes to a range of human diseases as a new mechanism of cell death. A previous study reported that pyroptosis plays an important role in immunity and diseases. Few studies have investigated the role of pyroptosis in glioma, and comprehensive analyses of pyroptosis regulators in glioma, their correlation with clinical characteristics and their prognostic value have not been reported
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