Dynamics of mitochondrial DNA copy number regulation in relation to gastric cancer survival.

[PURPOSE] To investigate the causal effects of gene expression levels associated with mitochondrial DNA copy number (mtDNA-CN) on cancer survival outcomes.

[METHODS] We performed two-sample mendelian randomization (MR) analyses to evaluate the causal relationship between mtDNA-CN in peripheral blood and overall survival period of different cancer types. Additionally, colocalization analyses were performed to identify genes whose expression correlates with mtDNA-CN. Furthermore, we investigated how expression levels of these genes impact survival period in different cancers.

[RESULTS] Higher mtDNA-CN in peripheral blood is significantly associated with reduced survival period in gastric cancer (HR = 72.97, 95% CI 68.86 to 77.08, p = 0.046). Colocalization analysis identified six genes, PNP, CDK10, C7orf73, NLRP2, MYO15A, and OSGEP, that regulate the mtDNA-CN in stomach tissue. Among them, higher expressions of MYO15A, OSGEP, and CDK10 are significantly associated with shorter gastric cancer survival. Notably, the impact of OSGEP expression on survival was particularly significant in the ERBB2 amplified subgroup (p = 0.025). Enrichment analysis suggests that the risk genes impact overall survival in gastric cancer prognosis by modulating mitochondrial function and DNA copy number.

[CONCLUSION] Higher mtDNA-CN in peripheral is correlated with the shorter overall survival in gastric cancer patient. Higher expression of MYO15A, OSGEP, and CDK10 is associated with shorter survival in gastric cancer patients, potentially by regulating mtDNA-CN, suggesting potential targets for future therapeutic interventions of gastric cancer.