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Genome Res. 2015 Jun;25(6):814-24. doi: 10.1101/gr.190470.115. Epub 2015 May 11.

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

Author information

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

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.

PMID:
25963125
PMCID:
PMC4448678
DOI:
10.1101/gr.190470.115
[Indexed for MEDLINE]
Free PMC Article

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