Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer

• Published in: PLoS genetics Vol. 8; no. 6; p. e1002689
• Main Authors: Ericson, Nolan G., Kulawiec, Mariola, Vermulst, Marc, Sheahan, Kieran, O'Sullivan, Jacintha, Salk, Jesse J., Bielas, Jason H.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2012; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; Biology; Cancer; Cell cycle; Colorectal cancer; Colorectal Neoplasms - genetics; Data processing; Deoxyribonucleic acid; Development and progression; DNA; DNA Damage - genetics; DNA, Mitochondrial - genetics; Evolution & development; Female; Fidelity; Genetic aspects; Genetic diversity; Genetic engineering; Genomes; Genomic Instability; Glucose - metabolism; Glycolysis; Glycolysis - genetics; Health aspects; Health sciences; Humans; Information management; Library collections; Male; Metastases; Metastasis; Middle Aged; Mitochondria; Mitochondrial DNA; Mutagenesis; Mutation; Nuclei; Organelles; Oxidative phosphorylation; Oxidative Stress; Oxygen; Physiological aspects; Point Mutation - genetics; Population; Reactive Oxygen Species - metabolism; Tumors; United States; Ireland
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1002689

Genome instability is regarded as a hallmark of cancer. Human tumors frequently carry clonally expanded mutations in their mitochondrial DNA (mtDNA), some of which may drive cancer progression and metastasis. The high prevalence of clonal mutations in tumor mtDNA has commonly led to the assumption that the mitochondrial genome in cancer is genetically unstable, yet this hypothesis has not been experimentally tested. In this study, we directly measured the frequency of non-clonal (random) de novo single base substitutions in the mtDNA of human colorectal cancers. Remarkably, tumor tissue exhibited a decreased prevalence of these mutations relative to adjacent non-tumor tissue. The difference in mutation burden was attributable to a reduction in C:G to T:A transitions, which are associated with oxidative damage. We demonstrate that the lower random mutation frequency in tumor tissue was also coupled with a shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, as compared to non-neoplastic colon. Together these findings raise the intriguing possibility that fidelity of mitochondrial genome is, in fact, increased in cancer as a result of a decrease in reactive oxygen species-mediated mtDNA damage.