Characterization of hypoxia-related molecular clusters and prognostic riskScore for glioma

Fang Xiang^1,2Xinhao Wu¹Chengran Xu^1*

• ¹Department of Neurosurgery, The First Affiliated Hospital of China Medical University, Shenyang, China
• ²Department of Neurosurgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China

Glioma, a prevalent CNS cancer, constitutes 30% of primary and 80% of malignant brain tumors.Incidence rises with age, slightly higher in males. High-grade gliomas, like GBM, are aggressive and life-threatening. Current treatments-surgery, radiation, chemotherapy-are limited, necessitating targeted therapies and deeper mechanistic insights for improved outcomes. Hypoxia, low oxygen tension, drives cancer progression via pathways like HIF, promoting angiogenesis, survival, and immune evasion. Targeting hypoxia is promising for therapy, as seen in breast, lung, and melanoma cancers. Advancing understanding of hypoxia in gliomas-its mechanisms, measurement, and targeted treatments-is critical for therapeutic innovation. Utilizing data from TCGA and CGGA, we classified gliomas into two subgroups, C1 and C2, based on hypoxia-related gene sets. Patients in the C1 subgroup exhibited significantly worse prognoses, with upregulated genes associated with multiple tumor progression pathways. Furthermore, the immune microenvironment in C1 was more conducive to tumor survival and growth. Genomic instability in C1 patients was markedly higher than in C2. A prognostic scoring system constructed using key hypoxia-related factors demonstrated robust prognostic value across multiple datasets. Finally, we identified four core hub genes (SOCS3, CLCF1, PLAUR, and LIF) that are likely overexpressed under hypoxic conditions, and their expression was validated via Western blot in glioma cell lines cultured under hypoxia. This study employed bioinformatics to subtype gliomas, revealing prognostic and functional differences, and experimentally validated the expression levels of candidate molecules, laying the groundwork for further research into their roles and mechanisms.