title: High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection.
abstract: 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.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98119, USA. hcoller@fhcrc.org
authors.forename: H A
authors.initials: HA
authors.lastname: Coller
authors.forename: K
authors.initials: K
authors.lastname: Khrapko
authors.forename: N D
authors.initials: ND
authors.lastname: Bodyak
authors.forename: E
authors.initials: E
authors.lastname: Nekhaeva
authors.forename: P
authors.initials: P
authors.lastname: Herrero-Jimenez
authors.forename: W G
authors.initials: WG
authors.lastname: Thilly
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000235:genetics; D003198:Computer Simulation; D004272:DNA, Mitochondrial; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation; D012641:Selection, Genetic
chemical_list: D004272:DNA, Mitochondrial