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.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Gastroenterology Libera Scientia Prague Czech Republic

Department of Genetics and Microbiology and Department of Physiology Faculty of Science Charles University Prague Czech Republic

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Internal Medicine University Hospital Motol 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Surgery 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Surgery Medical Faculty in Pilsen Charles University Pilsen Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Physiology 1st Faculty of Medicine Charles University Prague Czech Republic

Laboratory of Molecular Therapy Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Molecular Targets Program Center for Cancer Research Frederick MD USA

School of Pharmacy and Medical Science Griffith University Southport Qld Australia

Zobrazit více v PubMed

Abd Radzak SM, Mohd Khair SZN, Ahmad F, Patar A, Idris Z, Mohamed Yusoff AA. Insights regarding mitochondrial DNA copy number alterations in human cancer (Review). Int J Mol Med. 2022;50(2). 10.3892/ijmm.2022.5160. PubMed PMC

Akoglu H. User’s guide to correlation coefficients. Turk J Emerg Med. 2018;18(3):91–3. PubMed DOI PMC

van der Auwera G, O’Connor BD. Genomics in the cloud: using Docker, GATK, and WDL in Terra. O’Reilly Media, Incorporated; 2020.

Beckman KB, Ames BN. Oxidative decay of DNA. J Biol Chem. 1997;272(32):19633–6. PubMed DOI

Blair IA. DNA adducts with lipid peroxidation products. J Biol Chem. 2008;283(23):15545–9. PubMed DOI PMC

Boland ML, Chourasia AH, Macleod KF. Mitochondrial dysfunction in cancer. Front Oncol. 2013;3:292. PubMed DOI PMC

De Bont R, van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 2004;19(3):169–85. PubMed DOI

Brandt U. Energy converting nadh:quinone oxidoreductase (complex I). Annu Rev Biochem. 2006;75:69–92. PubMed DOI

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. PubMed

Chae YK, Anker JF, Carneiro BA, Chandra S, Kaplan J, Kalyan A, et al. Genomic landscape of DNA repair genes in cancer. Oncotarget. 2016;7(17):23312–21. PubMed DOI PMC

Chen T, He J, Huang Y, Zhao W. The generation of mitochondrial DNA large-scale deletions in human cells. J Hum Genet. 2011;56(10):689–94. PubMed DOI

Chen M, Deng S, Cao Y, Wang J, Zou F, Gu J, et al. Mitochondrial DNA copy number as a biomarker for guiding adjuvant chemotherapy in stages II and III colorectal cancer patients with mismatch repair deficiency: seeking benefits and avoiding harms. Ann Surg Oncol. 2024;31(9):6320–30. PubMed DOI PMC

Dani SU, Dani MA, Simpson AJ. The common mitochondrial DNA deletion deltamtDNA(4977): shedding new light to the concept of a tumor suppressor mutation. Med Hypotheses. 2003;61(1):60–3. PubMed DOI

Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010;18(6):884–901. PubMed DOI PMC

Ericson NG, Kulawiec M, Vermulst M, Sheahan K, O’Sullivan J, Salk JJ, et al. Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet. 2012;8(6):e1002689. PubMed DOI PMC

Filograna R, Mennuni M, Alsina D, Larsson NG. Mitochondrial DNA copy number in human disease: the more the better? FEBS Lett. 2021;595(8):976–1002. PubMed DOI PMC

Ho V, Chung L, Wilkinson K, Lea V, Lim SH, Abubakar A, et al. Prognostic significance of MRE11 overexpression in colorectal cancer patients. Cancers (Basel). 2023;15(9). 10.3390/cancers15092438. PubMed PMC

Huang B, Gao YT, Shu XO, Wen W, Yang G, Li G, et al. Association of leukocyte mitochondrial DNA copy number with colorectal cancer risk: results from the Shanghai women’s health study. Cancer Epidemiol Biomarkers Prev. 2014;23(11):2357–65. PubMed DOI PMC

Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66(18):8927–30. PubMed DOI

Kim YR, Chung NG, Kang MR, Yoo NJ, Lee SH. Novel somatic frameshift mutations of genes related to cell cycle and DNA damage response in gastric and colorectal cancers with microsatellite instability. Tumori. 2010;96(6):1004–9. PubMed

Kowalska M, Piekut T, Prendecki M, Sodel A, Kozubski W, Dorszewska J. Mitochondrial and nuclear DNA oxidative damage in physiological and pathological aging. DNA Cell Biol. 2020;39(8):1410–20. PubMed DOI

Lax NZ, Turnbull DM, Reeve AK. Mitochondrial mutations: newly discovered players in neuronal degeneration. Neuroscientist. 2011;17(6):645–58. PubMed DOI PMC

Leguisamo NM, Gloria HC, Kalil AN, Martins TV, Azambuja DB, Meira LB, et al. Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy. Oncotarget. 2017;8(33):54199–214. PubMed DOI PMC

Liao S, Chen L, Song Z, He H. The fate of damaged mitochondrial DNA in the cell. Biochimica et Biophysica Acta (BBA). 2022;1869(5):119233. PubMed DOI

Lin Y, Liao X, Zhang Y, Wu G, Ye J, Luo S, et al. Homologous recombination pathway alternation predicts prognosis of colorectal cancer with chemotherapy. Front Pharmacol. 2022;13:920939. PubMed DOI PMC

Naccarati A, Rosa F, Vymetalkova V, Barone E, Jiraskova K, Di Gaetano C, et al. Double-strand break repair and colorectal cancer: gene variants within 3’ UTRs and microRNAs binding as modulators of cancer risk and clinical outcome. Oncotarget. 2016;7(17):23156–69. PubMed DOI PMC

van Osch FH, Voets AM, Schouten LJ, Gottschalk RW, Simons CC, van Engeland M, et al. Mitochondrial DNA copy number in colorectal cancer: between tissue comparisons, clinicopathological characteristics and survival. Carcinogenesis. 2015;36(12):1502–10. PubMed

Papageorgiou SN. On correlation coefficients and their interpretation. J Orthod. 2022;49(3):359–61. PubMed DOI PMC

Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324–31. PubMed DOI

Potenza L, Calcabrini C, De Bellis R, Guescini M, Mancini U, Cucchiarini L, et al. Effects of oxidative stress on mitochondrial content and integrity of human anastomotic colorectal dehiscence: a preliminary DNA study. Can J Gastroenterol. 2011;25(8):433–9. PubMed DOI PMC

Qu F, Chen Y, Wang X, He X, Ren T, Huang Q, et al. Leukocyte mitochondrial DNA content: a novel biomarker associated with prognosis and therapeutic outcome in colorectal cancer. Carcinogenesis. 2015;36(5):543–52. PubMed DOI

Reznik E, Miller ML, Senbabaoglu Y, Riaz N, Sarungbam J, Tickoo SK et al. Mitochondrial DNA copy number variation across human cancers. Elife. 2016;5. 10.3892/ijmm.2022.5160 PubMed PMC

Sanz-Pamplona R, Berenguer A, Cordero D, Mollevi DG, Crous-Bou M, Sole X, et al. Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer. Mol Cancer. 2014;13:46. PubMed DOI PMC

Shinmura K, Kato H, Kawanishi Y, Igarashi H, Goto M, Tao H, et al. Abnormal expressions of DNA glycosylase genes NEIL1, NEIL2, and NEIL3 are associated with somatic mutation loads in human cancer. Oxid Med Cell Longev. 2016;2016:1546392. PubMed DOI PMC

Stein A, Sia EA. Mitochondrial DNA repair and damage tolerance. Front Biosci (Landmark Ed). 2017;22(5):920–43. PubMed DOI

Sun X, Zhan L, Chen Y, Wang G, He L, Wang Q, et al. Increased MtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer. Signal Transduct Target Ther. 2018;3:8. PubMed DOI PMC

Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM. Deficient mismatch repair/microsatellite unstable colorectal cancer: diagnosis, prognosis and treatment. Eur J Cancer. 2022;175:136–57. PubMed DOI

Tait SW, Green DR. Mitochondria and cell signalling. J Cell Sci. 2012;125(Pt 4):807–15. PubMed DOI PMC

Thyagarajan B, Guan W, Fedirko V, Barcelo H, Tu H, Gross M, et al. No association between mitochondrial DNA copy number and colorectal adenomas. Mol Carcinog. 2016;55(8):1290–6. PubMed DOI PMC

Vodenkova S, Jiraskova K, Urbanova M, Kroupa M, Slyskova J, Schneiderova M, et al. Base excision repair capacity as a determinant of prognosis and therapy response in colon cancer patients. DNA Repair. 2018;72:77–85. PubMed DOI

Vodicka P, Vodenkova S, Danesova N, Vodickova L, Zobalova R, Tomasova K et al. Mitochondrial DNA damage, repair, and replacement in cancer. Trends Cancer. 2024. 10.1016/j.trecan.2024.09.010 PubMed

Wallace L, Mehrabi S, Bacanamwo M, Yao X, Aikhionbare FO. Expression of mitochondrial genes MT-ND1, MT-ND6, MT-CYB, MT-COI, MT-ATP6, and 12S/MT-RNR1 in colorectal adenopolyps. Tumour Biol. 2016;37(9):12465–75. PubMed DOI PMC

Wang Y, He S, Zhu X, Qiao W, Zhang J. High copy number of mitochondrial DNA predicts poor prognosis in patients with advanced stage colon cancer. Int J Biol Markers. 2016;31(4):e382-8. PubMed DOI

Xu Y, Zhou J, Yuan Q, Su J, Li Q, Lu X, et al. Quantitative detection of Circulating MT-ND1 as a potential biomarker for colorectal cancer. Bosn J Basic Med Sci. 2021;21(5):577–86. PubMed PMC

Yang K, Li X, Forman MR, Monahan PO, Graham BH, Joshi A, et al. Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk. Carcinogenesis. 2019;40(12):1462–8. PubMed DOI PMC

Zhao YS, Hu FL, Wang F, Han B, Li DD, Li XW, et al. Meta-analysis of MSH6 gene mutation frequency in colorectal and endometrial cancers. J Toxicol Environ Health A. 2009;72(11–12):690–7. PubMed DOI

Annesley SJ, Fisher PR. Mitochondria in health and disease. Cells. 2019;8(7). 10.3390/cells8070680. PubMed PMC

Sharma P, Sampath H, Mitochondrial DNA, Integrity. Role Health Disease Cells. 2019;8(2). 10.3390/cells8020100 PubMed PMC