Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study.

BACKGROUND:  Investigating the role of mitochondrial DNA (mtDNA) alterations and their impact on brain tumor progression remains a significant focus in cancer research. The research aimed to explore the specific contributions of mtDNA copy number changes and their correlations with patient survival, large mtDNA deletions, and TFAM mutations in brain tumor patients. METHODS:  A total of 41 patients with confirmed brain tumors underwent DNA extraction from both tumor tissues and blood samples. The relative mtDNA copy number in comparison to the nuclear genome was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Long-range PCR assessed largescale mtDNA deletions, and Sanger sequencing was applied to detect exon 4 TFAM mutations. RESULTS:  Analysis revealed significantly increased mtDNA copy numbers in brain tumor tissues (80.5%) compared to matched blood samples (P < .001). Median delta Ct (∆Ct) values were 7.35 in cancerous tissues and 11.81 in blood (P <.001), with median relative mtDNA content of 0.0123 and 0.0006, respectively (P <.001). Patients with higher mtDNA copy numbers experienced longer overall survival periods (P=.045) and notably favorable outcomes, particularly in high-grade tumor cases (P=.016). Furthermore, a singlenucleotide deletion was identified in exon 4 of TFAM in a patient with glioblastoma IV, while no large-scale mtDNA deletions were found in brain tumor patients. CONCLUSION:  Our study strongly supports the role of increased mtDNA copy numbers as a reliable predictor for improved survival and positive outcomes in high-grade brain tumor patients.

The effect of somatic mutations in mitochondrial DNA on the survival of patients with primary brain tumors.

AIM: To assess the presence of mitochondrial (mt) DNA somatic mutations, determine the relationship between clinicopathological characteristics and mutations, and assess the survival outcomes in Malay patients with primary brain tumors. METHODS: The study enrolled 54 patients with primary brain tumors. DNA extracted from paired tissue and blood samples was subjected to Sanger sequencing to identify alterations in the entire mtDNA. The associations between clinicopathological characteristics and mutations were evaluated. Cox-regression multivariate analysis was conducted to identify factors significantly associated with survival, and Kaplan-Meier analysis was used to compare the survival of patients with and without mutations. RESULTS: Overall, 29.6% of the patients harbored 19 somatic mutations distributed across 15 loci within the mtDNA. Notably, 36.8% of these mutations were not previously documented in MITOMAP. One newly identified mutation caused a frameshift in the ATPase6 gene, resulting in a premature stop codon. Three mutations were classified as deleterious in the MitImpact2 database. Overall, 1097 mtDNA polymorphisms were identified across 331 different locations. Patients with mutations exhibited significantly shorter survival than patients without mutations. CONCLUSIONS: mtDNA mutations negatively affected the survival outcomes of Malaysian patients with primary brain tumors. However, studies with larger samples are needed to confirm the association between mutation burden and survival rates.