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BackgroundAlthough extensive researches related alternative splicing (AS) as the prognostic markers of patients in cancers, which remains unknown in clear cell renal cell carcinoma (ccRCC), especially in immunotherapy. Therefore, a novel survival-associated AS signature was established to predict prognosis of patients and explored its correlation with immune cell infiltration or immune checkpoint expression to explain the phenomenon of resistance to immunotherapy in ccRCC.Methodsccording to AS data, clinical information and gene expression data in ccRCC, overall survival-related AS events was identified and further the AS-related prognostic risk model established by LASSO regression and multi-Cox regression analysis was evaluated by Kaplan-Meier survival analysis, the ROC curves and a nomogram model. Then we clarified the biological processes and pathways by GSEA, and further measured the immune cell infiltration by ESTIMATE, CIBERSORT and ssGSEA. Finally we analysed the clinical features and immune features of different parental genes, and quested the splicing factors regulating riskScore-related AS events by Spearman correlation analysis.ResultsWe obtained the most significant 5 AS events, including C4orf19|69001|AT, UACA|31438|AP, FAM120C|89237|AT, TRIM16L|39629|AP and SEC31A|100881|ES, to establish the prognostic risk model, and further illustrated the stability and importance of the riskScore prognostic signatures. Then we found that in high risk group, most of the top 10 GO enrichments and the KEGG pathway were closely related to the immunity, and the higher immune cell infiltration, and higher expression of classic immune checkpoints such as PD1 and CTLA4. In addition, 6 different parental genes were obtained, including C4orf19, ARHGAP24 DNASE1L3, P4HA1, SLC39A14 and TAF1D. These 6 genes could not be the independent prognostic signatures, but the expression of these genes was closely related to immune cells infiltration and the expression of immune checkpoints. Finally, we got aberrant 52 splicing factors regulating riskScore-related AS events.ConclusionOur study discovered that overall survival-related AS events mediated by aberrant splicing factors can be constructed a prognostic risk model to predict prognosis of patiens and utilized to index the situation of immune cell infiltration and immune checkpoint expression that impact tumor immune microenvironment in ccRCC.

Background: About 90% renal malignancies are RCCs (renal cell carcinomas) and the main subtype in histology is ccRCC (clear cell RCC). In recent years, pyroptosis was considered as a kind of inflammation-related programmed cell death, which played a part in the invasion, metastasis and proliferation of tumor cells, thereby influencing tumor prognosis. Nonetheless, the expression level of pyroptosis-associated genes in RCCs and its relationship with prognosis are still not clear. Results: In our research, 44 regulators for pyroptosis were identified which were expressed differentially between normal kidney and ccRCC tissues. ccRCC cases were categorized into 2 subgroups with a significant difference between them in OS (overall survival) according to the DEGs (differentially expressed genes). The prognostic value of pyroptosis-associated genes was assessed as a signature based on the cohort of TCGA (The Cancer Genome Atlas). Following Cox regression with DEGs and LASSO (least absolute shrinkage and selection operator), a 6-gene signature had been set up and all the ccRCC cases in the cohort of TCGA were categorized into LR (low-risk) group or HR (high-risk) group (P < 0.001). In combination with clinical features, risk scores were considered as a predicting factor of OS in ccRCC cases. KEGG (Kyoto Encylopedia of Genes and Genomes) and GO (Gene ontology) analyses implied increased immunity and enrichment of genes related to immunity in the HR group. Conclusions: Our findings indicated that the genes related to pyroptosis had an important role in tumor immunity, which were potentially used to predict the prognosis of ccRCCs.