Dysregulated mitochondrial homeostasis and DNA repair in the progression from colon adenoma to cancer

BACKGROUND: While nuclear DNA (nDNA) damage and alterations in nDNA repair are known to play a role in colon cancer (CC), there is insufficient research investigating these processes in mitochondrial DNA (mtDNA). METHODS: This study investigates mtDNA changes in CC, focusing on mitochondrial DNA copy number (mtDNA-CN) variations, mtDNA damage, and the expression and mutation status of DNA repair genes. Three cohorts were analyzed: healthy controls, colon adenoma patients, and CC patients, divided into a pilot and a validation set. RESULTS: Our findings revealed that mtDNA-CN was elevated in colon adenomas compared to adenoma-adjacent mucosa (FDR = 0.04), healthy mucosa (FDR = 0.005), and tumor-adjacent mucosa (FDR = 0.005). Moreover, mtDNA-CN was elevated in adenoma-adjacent mucosa compared to healthy mucosa (FDR = 0.04). MtDNA damage was greater in tumor-adjacent mucosa compared to tumor tissue in both the pilot and validation sets (FDR = 0.031 and FDR = 2.06e-05, respectively). Additionally, we identified novel DNA repair genes associated with mtDNA damage, predominantly upregulated in adenoma and tumor tissues compared to healthy colon tissues. CONCLUSIONS: To conclude, this study highlights the importance of mtDNA alterations in CC development and identifies potential mtDNA biomarkers.