Comprehensive Characterization Of Ferroptosis And Pyroptosis In Lowgrade Glioma Identifies A Novel Prognostic Signature For Predicting Clinical Outcomesand Immunotherapy Responses

Background: Accumulating evidence reveals that ferroptosis and pyroptosis play pivotal roles in tumorigenesis of low-grade glioma(LGG).Iron mediated lipid peroxide-driven cell death response has been an important target of anti-tumor therapy in the world.Changes in cellular protein expression in gliomas and their regulation of tumor activity are supported by ample evidence.In 2021,the World Health Organization(WHO)classification of central nervous system tumors was integrated with the information of the Central Nervous System Tumor Molecular Information and Classification Practice Alliance,and the importance of molecular diagnosis was particularly pointed out.IDH wild-type diffuse astrocytoma with histological appearance of CNS WHO grade 2 can also be diagnosed as glioblastoma if it is accompanied by genetic mutation or partial chromosomal deletion(chromosome 10 deletion),and the molecular variation features It is also a related prognostic marker.Due to the rapid proliferation of LGG and its poor sensitivity to chemotherapeutic drugs,surgical treatment cannot completely solve the tumor invasion of normal nerve cells,and the functional area is too small.At present,there is evidence that immunotherapy can activate CD8+ T cells to cause iron ion lipid-specific peroxidation of tumor cells,which means that ferroptosis will enhance the efficacy of anti-tumor immunotherapy.It is well known that in the immune response,the immune system continuously achieves immune fine-tuning to adapt to changes in the tumor microenvironment(TME).Cytokines produced by pyroptosis can mediate programmed cell death(PCD)and are also a "double-edged sword" that elicits tumor immune responses.In recent years,we have focused on the role of pyroptosis in immunotherapy and its use as a target therapy.Based on the above,ferroptosis and pyroptosis are both PCD modes,and several studies have confirmed the crosstalk between these two cell death modes,so the genes associated with the two are worthy of study as markers of clinical prediction and immune response.Bioinformatics spans the disciplines of biology,informatics,mathematics,medicine and other disciplines.In the era of big data,we urgently need to explore new biomarkers or early prognostic features of LGG.Objective: In this research,we aimed to classify molecular subtypes and further identify and verify a novel multigene signature to anticipate the prognosis and immunotherapy response of LGG patients on the basis of ferroptosis and pyroptosis-related genes(FPRG).Methods: Raw sequencing data and corresponding clinical data of LGG samples retrieved from the TCGA and CGGA databases were obtained for the training and validation datasets.Non-negative matrix factorization(NMF)clustering defined by FPRG associated with prognosis was performed to classify molecular subtypes of LGG patients.LASSO-SVMrandom Forest analysis was carried out to filter genes and further develop and validate a novel FPRG signature to predict the survival and benefit of immunotherapy of LGG patients.Results: 87 shared FPRG genes with prognostic values were acquired in both training and validation datasets.NMF clustering defined by these FPRGs acted to categorize LGG patients into two molecular subtypes with significantly different prognosis,clinical traits,and immune microenvironments.After performing LASSO-SVM-random Forest analysis,a novel sixFPRG prognostic signature was constructed accompanied by the optimal p-value.The AUC values of our FPRG signature exhibited great prognostic performances in both training and validation datasets.Our FPRG signature was superior to another four well-recognized signatures in predicting the survival probability of LGG patients.Immune cell infiltration,immune checkpoint gene expression,immune subtype identification,tumor mutation profile,tumor stemness indices,MGMT methylation,and immunotherapy response biomarkers showed significant differences between high-and low-risk populations,which provided an essential grounding for immunotherapy response prediction.High-risk LGG populations exhibited increased levels of CD8,CD274,IFNG,Merck18,and decreased scores of MDSC and T cell exclusion,thereby more likely benefiting from immunotherapy.Finally,a nomogram comprising tumor type,gender,age,cancer status,grade,and FPRG score was created and validated for quantitative prediction of the survival probability of LGG patients,and the AUC values of the nomogram were 0.916,0.888,and 0.836 for 1-,3-,and 5-year survival,sequentially.Conclusion: Overall,the FPRG signature may function as an effective indicator for predicting the prognosis and immunotherapy response of LGG patients.