Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

  1. Michael R. Stratton1
  1. 1Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
  2. 2Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
  3. 3Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom;
  4. 4Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
  5. 5Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom;
  6. 6BioCare, Strategic Cancer Research Program, SE-223 81 Lund, Sweden;
  7. 7CREATE Health, Strategic Centre for Translational Cancer Research, SE-221 00 Lund, Sweden;
  8. 8Department of Oncology and Pathology, Lund University Cancer Center, SE-221 85 Lund, Sweden;
  9. 9Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom;
  10. 10Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, 230-0045 Yokohama, Japan;
  11. 11National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan;
  12. 12Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA;
  13. 13Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands;
  14. 14Department of General Surgery, Singapore General Hospital, Singapore 169608;
  15. 15Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada;
  16. 16Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, 6525 HP Nijmegen, Netherlands;
  17. 17Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands;
  18. 18Section of Oncology, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway;
  19. 19Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway;
  20. 20Institut Curie, INSERM U934 and Department of Tumor Biology, 75248 Paris cédex 05, France;
  21. 21Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway;
  22. 22The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway;
  23. 23Cancer Research Laboratory, University of Iceland, 101 Reykjavik, Iceland;
  24. 24Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, Nydalen 0424 Oslo, Norway;
  25. 25Royal National Orthopaedic Hospital, Middlesex HA7 4LP, United Kingdom;
  26. 26UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom;
  27. 27University of Liverpool and HCA Pathology Laboratories, London WC1E 6JA, United Kingdom;
  28. 28Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge CB2 0RE, United Kingdom;
  29. 29Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom;
  30. 30Institute of Cancer Research, Sutton, London SM2 5NG, United Kingdom;
  31. 31Department of Biological Sciences and School of Medicine, University of East Anglia, Norwich NR4 7TJ, United Kingdom;
  32. 32Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, United Kingdom;
  33. 33Royal Marsden NHS Foundation Trust, London SW3 6JJ and Sutton SM2 5PT, United Kingdom;
  34. 34Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere and Tampere University Hospital, 33520 Tampere, Finland;
  35. 35University of Queensland, School of Medicine, Brisbane, QLD 4006, Australia;
  36. 36Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia;
  37. 37University of Queensland, UQ Centre for Clinical Research, Brisbane, QLD 4029, Australia;
  38. 38Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, 1000 Brussels, Belgium;
  39. 39Université Lyon 1, Institut National du Cancer (INCa)–Synergie, 69008 Lyon, France;
  40. 40Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
  41. 41Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
  42. 42Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom;
  43. 43Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  1. Corresponding author: mrs{at}sanger.ac.uk

  1. ↵45 These authors contributed equally to this work.

  • ↵44 Deceased.

Abstract

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

Footnotes

  • ↵46 A full list of members is provided in the Supplemental Material.

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.190470.115.

  • Freely available online through the Genome Research Open Access option.

  • Received February 3, 2015.
  • Accepted April 14, 2015.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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  1. Published in Advance May 11, 2015, doi: 10.1101/gr.190470.115 Genome Res. 25: 814-824 © 2015 Ju et al.; Published by Cold Spring Harbor Laboratory Press

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