title: Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.
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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Ju
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Jose M C
authors.initials: JM
authors.lastname: Tubio
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: William
authors.initials: W
authors.lastname: Mifsud
authors.affiliation: Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Beiyuan
authors.initials: B
authors.lastname: Fu
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Helen R
authors.initials: HR
authors.lastname: Davies
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Lucy
authors.initials: L
authors.lastname: Yates
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Sam
authors.initials: S
authors.lastname: Behjati
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Anthony
authors.initials: A
authors.lastname: Fullam
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Moritz
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: 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;
authors.forename: Jyoti
authors.initials: J
authors.lastname: Nangalia
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom; Department of Haematology, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.affiliation: 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;
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: 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;
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Breakthrough Breast Cancer Research Unit, Research Oncology, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Tutt
authors.affiliation: 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;
authors.forename: Ming Ta Michael
authors.initials: MT
authors.lastname: Lee
authors.affiliation: 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;
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van't Veer
authors.affiliation: Department of General Surgery, Singapore General Hospital, Singapore 169608;
authors.forename: Benita K T
authors.initials: BK
authors.lastname: Tan
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver V5Z 1L3, Canada;
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, 6525 HP Nijmegen, Netherlands;
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands;
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway; Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway;
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Institut Curie, INSERM U934 and Department of Tumor Biology, 75248 Paris cédex 05, France;
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: 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;
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Cancer Research Laboratory, University of Iceland, 101 Reykjavik, Iceland;
authors.forename: Jórunn Erla
authors.initials: JE
authors.lastname: Eyfjörd
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Royal National Orthopaedic Hospital, Middlesex HA7 4LP, United Kingdom; UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom;
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: University of Liverpool and HCA Pathology Laboratories, London WC1E 6JA, United Kingdom;
authors.forename: Christopher
authors.initials: C
authors.lastname: Foster
authors.affiliation: 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;
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: 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;
authors.forename: Colin
authors.initials: C
authors.lastname: Cooper
authors.affiliation: 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;
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.forename: Steven G
authors.initials: SG
authors.lastname: Bova
authors.affiliation: 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;
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Lakhani
authors.affiliation: Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, 1000 Brussels, Belgium;
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: Université Lyon 1, Institut National du Cancer (INCa)-Synergie, 69008 Lyon, France;
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom;
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Cytogenetics Facility, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Fengtang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D056915:DNA Copy Number Variations; D059766:DNA End-Joining Repair; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D015894:Genome, Human; D054629:Genome, Mitochondrial / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008928:Mitochondria / Q000235:genetics; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial