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

Researchers in several laboratories have reported a high frequency of homop lasmic mitochondrial DNA (mtDNA) mutations in human tumors(1-6). This obser vation has been interpreted to reflect a replicative advantage for mutated mtDNA copies(1,2,6), a growth advantage for a cell containing certain mtDNA mutations(1,6), and/or tumorigenic properties of mtDNA mutations(2). We co nsider another possibility-that the observed homoplasmy arose entirely by c hance in tumor progenitor cells, without any physiological advantage or tum origenic requirement. Through extensive computer modeling, we demonstrate t hat there is sufficient opportunity for a tumor progenitor cell to achieve homoplasmy through unbiased mtDNA replication and sorting during cell divis ion. To test our model in vivo, we analyzed mtDNA homoplasmy in healthy hum an epithelial tissues and discovered that the model correctly predicts the considerable observed frequency of homoplasmic cells. Based on the availabl e data on mitochondrial mutant fractions and cell division kinetics, we sho w that the predicted frequency of homoplasmy in tumor progenitor cells in t he 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 mt DNA mutations in human tumors.