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Background <p>Gliomas represent the most prevalent and aggressive primary brain tumors in adults. Accumulating data suggest a strong connection between mitochondrial dysfunction and cancer development. However, signature markers for assessing mitochondrial genetic risk in human glioma remain limited. This study aims to identify mitochondrial genes associated with glioma patient prognosis, develop a strong mitochondrial-related gene signature (MRGS), and analyze the tumor immune microenvironment (TIME) related to this signature. The expression profiles and prognostic value of MRGS were analyzed using R language, GraphPad Prism 8 and online databases.</p> Results <p>A signature of seven genes including ACSL1, NOX4, ALDH3A2, ALKBH4, FASTK, FDX1, ACADVL was constructed using the TCGA cohort and further validated in an independent CGGA cohort. Our result showed that the mitochondrial signature was significantly associated with high-grade and isocitrate dehydrogenase (IDH) wild-type gliomas, aggressive molecular and histological features, and poor survival. Subgroup analyses demonstrated that the risk signature was significantly associated with overall survival (OS) across WHO tumor grades and IDH mutation status, suggesting added prognostic value beyond established clinical markers. Additionally, the risk signature demonstrated a significant difference in immune cell infiltration between the high-risk (H-R) and low-risk (L-R) groups. Moreover, the risk score was strongly correlated with tumor microenvironment (TME)-related marker and immune checkpoint molecules such as (PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, BTLA, HVEM, NR2F6), suggesting that an immunosuppressive TME could lead to a poor prognosis in H-R groups. Additionally, Multivariable Cox analysis showed that risk score was an independent predictor of poor prognosis in both TCGA (Hazard Ratio (HR) = 2.17, 95% confidence interval (CI): 1.44–3.3, <i>p</i> &lt; 0.001) and CGGA (HR = 2.07, 95% CI: 1.49–2.88 <i>p</i> &lt; 0.001) datasets. Finally, enrichment analysis highlighted the association of the signature with biological mechanisms involved in tumor progression.</p> Conclusion <p>Our findings suggest a novel mitochondrial-related gene signature for the TIME that could be used as a reliable prognostic biomarker for patients with glioma.</p>

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A novel mitochondrial-related gene signature for assessing the tumor immune microenvironment and predicting prognosis in human glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Zakia Harmak,
  • Oumayma Naji,
  • Hamza Baddi,
  • Bouchra Ghazi,
  • Abdallah Badou

摘要

Background

Gliomas represent the most prevalent and aggressive primary brain tumors in adults. Accumulating data suggest a strong connection between mitochondrial dysfunction and cancer development. However, signature markers for assessing mitochondrial genetic risk in human glioma remain limited. This study aims to identify mitochondrial genes associated with glioma patient prognosis, develop a strong mitochondrial-related gene signature (MRGS), and analyze the tumor immune microenvironment (TIME) related to this signature. The expression profiles and prognostic value of MRGS were analyzed using R language, GraphPad Prism 8 and online databases.

Results

A signature of seven genes including ACSL1, NOX4, ALDH3A2, ALKBH4, FASTK, FDX1, ACADVL was constructed using the TCGA cohort and further validated in an independent CGGA cohort. Our result showed that the mitochondrial signature was significantly associated with high-grade and isocitrate dehydrogenase (IDH) wild-type gliomas, aggressive molecular and histological features, and poor survival. Subgroup analyses demonstrated that the risk signature was significantly associated with overall survival (OS) across WHO tumor grades and IDH mutation status, suggesting added prognostic value beyond established clinical markers. Additionally, the risk signature demonstrated a significant difference in immune cell infiltration between the high-risk (H-R) and low-risk (L-R) groups. Moreover, the risk score was strongly correlated with tumor microenvironment (TME)-related marker and immune checkpoint molecules such as (PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, BTLA, HVEM, NR2F6), suggesting that an immunosuppressive TME could lead to a poor prognosis in H-R groups. Additionally, Multivariable Cox analysis showed that risk score was an independent predictor of poor prognosis in both TCGA (Hazard Ratio (HR) = 2.17, 95% confidence interval (CI): 1.44–3.3, p < 0.001) and CGGA (HR = 2.07, 95% CI: 1.49–2.88 p < 0.001) datasets. Finally, enrichment analysis highlighted the association of the signature with biological mechanisms involved in tumor progression.

Conclusion

Our findings suggest a novel mitochondrial-related gene signature for the TIME that could be used as a reliable prognostic biomarker for patients with glioma.