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Identifying Diffuse Glioma Subtypes Based on Pathway Enrichment Evaluation

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Abstract

Gliomas are highly heterogeneous in molecular, histology, and microenvironment. However, a classification of gliomas by integrating different tumor microenvironment (TME) components remains unexplored. Based on the enrichment scores of 17 pathways involved in immune, stromal, DNA repair, and nervous system signatures in diffuse gliomas, we performed consensus clustering to uncover novel subtypes of gliomas. Consistently in three glioma datasets (TCGA-glioma, CGGA325, and CGGA301), we identified three subtypes: Stromal-enriched (Str-G), Nerve-enriched (Ner-G), and mixed (Mix-G). Ner-G was charactered by low immune infiltration levels, stromal contents, tumor mutation burden, copy number alterations, DNA repair activity, cell proliferation, epithelial-mesenchymal transformation, stemness, intratumor heterogeneity, androgen receptor expression and EGFR, PTEN, NF1 and MUC16 mutation rates, while high enrichment of neurons and nervous system pathways, and high tumor purity, estrogen receptor expression, IDH1 and CIC mutation rates, temozolomide response rate and overall and disease-free survival rates. In contrast, Str-G displayed contrastive characteristics to Ner-G. Our analysis indicates that the heterogeneity between glioma cells and neurons is lower than that between glioma cells and immune and stromal cells. Furthermore, the abundance of neurons is positively associated with clinical outcomes in gliomas, while the enrichment of immune and stromal cells has a negative association with them. Our classification method provides new insights into the tumor biology of gliomas, as well as clinical implications for the precise management of this disease.

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All data associated with this study are available within the paper and its supplementary data.

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Funding

This work was supported by the China Pharmaceutical University (grant number 3150120001 to XW).

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Author notes

  1. Qiushi Feng and Zehua Dong are equal contribution.

Authors and Affiliations

  1. Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Qiushi Feng, Zehua Dong, Rongfang Nie & Xiaosheng Wang

  2. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China

    Qiushi Feng, Zehua Dong, Rongfang Nie & Xiaosheng Wang

  3. Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China

    Qiushi Feng, Zehua Dong, Rongfang Nie & Xiaosheng Wang

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  1. Qiushi Feng
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Contributions

QF performed the research, data analyses, and manuscript writing. ZD performed the research, data analyses, and manuscript editing. RN preformed data analyses and manuscript editing. XW conceived this study, designed analysis strategies, and wrote the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Xiaosheng Wang.

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Feng, Q., Dong, Z., Nie, R. et al. Identifying Diffuse Glioma Subtypes Based on Pathway Enrichment Evaluation. Interdiscip Sci Comput Life Sci (2024). https://doi.org/10.1007/s12539-024-00627-w

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