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

Nature Genetics volume 28, pages 147–150 (2001)Cite this article

Abstract

Researchers in several laboratories have reported a high frequency of homoplasmic mitochondrial DNA (mtDNA) mutations in human tumors1,2,3,4,5,6. This observation has been interpreted to reflect a replicative advantage for mutated mtDNA copies1,2,6, a growth advantage for a cell containing certain mtDNA mutations1,6, and/or tumorigenic properties of mtDNA mutations2. 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.

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Figure 1: Expected dynamics of attaining homoplasmy by somatic mtDNA mutations in a continuous cell lineage.
Figure 2: Probability that a tumor will contain at least one homoplasmic mtDNA mutant.
Figure 3: Comparison of the predicted and experimentally measured fraction of tumors with different numbers of homoplasmic mitochondrial mutants per tumor.
Figure 4: Effects of varying the number of mitochondria per cell on the probability of homoplasmy.

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Acknowledgements

We thank M. Strumia, T. Knight and M. Eberle for technical assistance; P. Sheridan for assistance obtaining samples; L. Kruglyak, J. Roberts, B. Coller, E. Steiner, J. Wei, E. Giniger and A.D.N.J. deGrey for critical comments on the manuscript; and S. Kruglyak, P. André and other members of the Thilly laboratory for helpful discussions. The research reported here was supported by grants from the National Institute of Environmental Health Sciences (P30-ES02109, P01-ES07168 and P42-ES04675 to W.G.T.) and the National Institute of Aging (T32-AG00251 to E.N. and R03-AG18536 and R01-AG18388 to K.K.). H.A.C. is a Jane Coffin Child Memorial Fund postdoctoral fellow.

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Authors and Affiliations

  1. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98119, Washington, USA

    Hilary A. Coller

  2. Beth Deaconess Israel Medical Center and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Konstantin Khrapko, Natalya D. Bodyak & Ekaterina Nekhaeva

  3. Division of Bioengineering and Environmental Health, Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Pablo Herrero-Jimenez & William G. Thilly

Authors
  1. Hilary A. Coller
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  2. Konstantin Khrapko
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  4. Ekaterina Nekhaeva
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  5. Pablo Herrero-Jimenez
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  6. William G. Thilly
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Correspondence to Hilary A. Coller.

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Coller, H., Khrapko, K., Bodyak, N. et al. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 28, 147–150 (2001). https://doi.org/10.1038/88859

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