Mitochondrial DNA Haplogroups and SNPs: Risk Factors in Multiple Cancers Based on a Cross-Tumor Analysis in Chinese Population

Abstract Background: Mitochondrial DNA's (mtDNA) haplogroups and SNPs were associated with the risk of different cancer. However, there is no evidence that the same haplogroup or mitochondrial SNP (mtSNP) exhibits the pleiotropic effect on multiple cancers. Methods: We recruited 2,489 participants, including patients with colorectal, hepatocellular, lung, ovarian, bladder, breast, pancreatic, and renal cell carcinoma. In addition, 715 healthy individuals from Northern China served as controls. Next, cross-tumor analysis was performed to determine whether mtDNA variation is associated with multiple cancers. Results: Our results revealed a significant decrease in the occurrence risk of multiple cancers among individuals belonging to haplogroup A [OR = 0.553, 95% confidence interval (CI) = 0.375–0.815, P = 0.003]. Furthermore, we identified 11 mtSNPs associated with multiple cancers and divided the population into high-risk and low-risk groups. Low-risk groups showed a significantly reduced risk of occurrence compared with high-risk groups (OR = 0.614, 95% CI = 0.507–0.744, P < 0.001). Furthermore, using interaction analysis, we identified a special group of individuals belonging to haplogroup A/M7 and the low-risk population, who exhibit a lower risk of multiple cancers compared with other populations (OR = 0.195, 95% CI = 0.106–0.359, P < 0.001). Finally, gene set enrichment analysis confirmed that haplogroup A/M7 patients had lower expression levels of cancer-related pathway genes compared with haplogroup D patients. Conclusions: We found that specific mtDNA haplogroups and mtSNPs may play a role in predicting multiple cancer predisposition in Chinese populations. Impact: This may provide a potential tool for early screening in clinical settings for individuals in the Chinese population.