Background: Recent discoveries have revealed that fibronectin type III domain containing 3B (FNDC3B) acts as an oncogene in various cancers; however, its role in glioma remains unclear. Methods: In this study, we comprehensively investigated the expression, prognostic value, and immune significance of FNDC3B in glioma using several databases and bioinformatics analysis. RNA expression data and clinical information of 529 patients from the Cancer Genome Atlas (TCGA) and 1319 patients from

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... Glioma Genome Atlas (CGGA) databases were downloaded for further investigation. A nomogram model based on TCGA low-grade glioma (LGG) dataset was constructed to assess the prognosis value of FNDC3B in glioma by plotting calibration, K-M, and receiver operating characteristic (ROC) curves. The predicted nomogram was validated by CGGA cohorts. Differentially expressed genes (DEGs) were detected by the Wilcoxon test based on the TCGA-LGG dataset and the weighted gene co-expression network analysis (WGCNA) was implemented to identify the significant module associated with the expression level of FNDC3B. Furthermore, we investigated the correlation between FNDC3B with cancer immune infiltrates using TISIDB, ESTIMATE, and CIBERSORTx.Results: Higher FNDC3B expression displayed a remarkably worse overall survival and the expression level of FNDC3B was an independent prognostic indicator for patients with glioma. Based on TCGA LGG dataset, a co-expression network was established and the hub genes were identified. FNDC3B expression was positively correlated to the tumor-infiltrating lymphocytes and immune infiltration score, and high FNDC3B expression was accompanied by the increased expression of B7-H3, PD-L1, TIM-3, PD-1, and CTLA-4. Moreover, expression of FNDC3B was significantly associated with infiltrating levels of several types of immune cells and most of their gene markers in glioma. Conclusion: This study demonstrated that FNDC3B may be involved in the occurrence and development of glioma and can be regarded as a promising prognostic and immunotherapeutic biomarker for the treatment of glioma.