High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection

• Published in: Nature genetics Vol. 28; no. 2; pp. 147 - 150
• Main Authors: Nekhaeva, Ekaterina, Thilly, William G, Khrapko, Konstantin, Herrero-Jimenez, Pablo, Coller, Hilary A, Bodyak, Natalya D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.06.2001
• Subjects: Aged; Aged, 80 and over; Biological and medical sciences; Cell division; Classical genetics, quantitative genetics, hybrids; Colonic Neoplasms - genetics; Computer Simulation; DNA, Mitochondrial; Environmental health; Epithelial Cells - physiology; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Human; Humans; Middle Aged; Mitochondrial DNA; Models, Biological; Mutation; Neoplasms - genetics; Physiological aspects; Point Mutation; Publishing; Selection, Genetic; Stem cells; Tumors; United States; United States > US; Massachusetts; Human; Tumor; Mitochondrial DNA; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/88859

Researchers in several laboratories have reported a high frequency of homoplasmic mitochondrial DNA (mtDNA) mutations in human tumors. This observation has been interpreted to reflect a replicative advantage for mutated mtDNA copies, a growth advantage for a cell containing certain mtDNA mutations, and/or tumorigenic properties of mtDNA mutations. We consider another possibility-that the observed homoplasmy arose entirely by chance in tumor progenitor cells, without any physiological advantage or tumorigenic requirement. Through extensive computer modeling, we demonstrate that there is sufficient opportunity for a tumor progenitor cell to achieve homoplasmy through unbiased mtDNA replication and sorting during cell division. To test our model in vivo, we analyzed mtDNA homoplasmy in healthy human epithelial tissues and discovered that the model correctly predicts the considerable observed frequency of homoplasmic cells. Based on the available data on mitochondrial mutant fractions and cell division kinetics, we show that the predicted frequency of homoplasmy in tumor progenitor cells in the absence of selection is similar to the reported frequency of homoplasmic mutations in tumors. Although a role for other mechanisms is not excluded, random processes are sufficient to explain the incidence of homoplasmic mtDNA mutations in human tumors.