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Introduction <p>Glioma, especially glioblastoma (GBM), has a dismal prognosis with current therapies. In this study, we aimed to identify potential novel molecular targets for GBM by analyzing RNA sequencing.</p> Methods <p>RNA-seq data from TCGA, CGGA, and GTEx were analyzed to assess <i>DENND2D</i> expression across glioma grades and molecular subtypes. Survival analysis, methylation/copy number profiling, weighted gene co-expression network analysis (WGCNA), functional enrichment (GO/KEGG), and immune infiltration deconvolution (CIBERSORT) were performed.</p> Results <p>By multi-cohort analysis, 5 upregulated genes and 23 downregulated genes demonstrated prognostic significance in GBM. <i>DENND2D</i> was upregulated in high-grade gliomas (GBM &gt; LGG; <i>p</i> &lt; 0.05) and correlated with poor prognostic features (IDH-wildtype, non-1p/19q-codeletion). High <i>DENND2D</i> levels predicted worse survival (HR &gt; 1, <i>p</i> &lt; 0.001) in TCGA and CGGA cohorts. Expression was inversely correlated with promoter methylation (sites cg00619207/cg24641737) and was modulated by copy number alterations. WGCNA revealed co-expression with immune regulators (RAC2/TLR2/ITGB2/PTPRC/HLA-DPA1) and enrichment in leukocyte activation pathways (<i>p</i> &lt; 0.01). CIBERSORT showed that <i>DENND2D</i>^high tumors had elevated immunosuppressive infiltrates: M1/M2 macrophages and γδ T cells in LGG, and M2 macrophages in GBM (<i>p</i> &lt; 0.05).</p> Conclusion <p><i>DENND2D</i> acts as an oncogene in glioma, driving aggressiveness and shaping an immunosuppressive microenvironment. It represents a novel prognostic biomarker and therapeutic target for overcoming immunotherapy resistance.</p>

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DENND2D serves as a novel prognostic biomarker with paradoxical protumorigenic effects in glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月8日

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  • Hongxing Ye,
  • Chao Zhang,
  • Linghao Bu,
  • Feng Xiao,
  • Yuxiang Weng,
  • Kaiyuan Huang,
  • Zebin Fang,
  • Weijian Fan,
  • Hao Jiang,
  • Yu Zhu,
  • Renya Zhan,
  • Xiujue Zheng,
  • Yumin Wang,
  • Zhouying Peng,
  • Luyuan Zhang

摘要

Introduction

Glioma, especially glioblastoma (GBM), has a dismal prognosis with current therapies. In this study, we aimed to identify potential novel molecular targets for GBM by analyzing RNA sequencing.

Methods

RNA-seq data from TCGA, CGGA, and GTEx were analyzed to assess DENND2D expression across glioma grades and molecular subtypes. Survival analysis, methylation/copy number profiling, weighted gene co-expression network analysis (WGCNA), functional enrichment (GO/KEGG), and immune infiltration deconvolution (CIBERSORT) were performed.

Results

By multi-cohort analysis, 5 upregulated genes and 23 downregulated genes demonstrated prognostic significance in GBM. DENND2D was upregulated in high-grade gliomas (GBM > LGG; p < 0.05) and correlated with poor prognostic features (IDH-wildtype, non-1p/19q-codeletion). High DENND2D levels predicted worse survival (HR > 1, p < 0.001) in TCGA and CGGA cohorts. Expression was inversely correlated with promoter methylation (sites cg00619207/cg24641737) and was modulated by copy number alterations. WGCNA revealed co-expression with immune regulators (RAC2/TLR2/ITGB2/PTPRC/HLA-DPA1) and enrichment in leukocyte activation pathways (p < 0.01). CIBERSORT showed that DENND2D^high tumors had elevated immunosuppressive infiltrates: M1/M2 macrophages and γδ T cells in LGG, and M2 macrophages in GBM (p < 0.05).

Conclusion

DENND2D acts as an oncogene in glioma, driving aggressiveness and shaping an immunosuppressive microenvironment. It represents a novel prognostic biomarker and therapeutic target for overcoming immunotherapy resistance.