1. Genetics and Genomics
  2. Cancer Biology
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Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

  1. Young Seok Ju
  2. Ludmil B Alexandrov
  3. Moritz Gerstung
  4. Inigo Martincorena
  5. Serena Nik-Zainal
  6. Manasa Ramakrishna
  7. Helen R Davies
  8. Elli Papaemmanuil
  9. Gunes Gundem
  10. Adam Shlien
  11. Niccolo Bolli
  12. Sam Behjati
  13. Patrick S Tarpey
  14. Jyoti Nangalia
  15. Charles E Massie
  16. Adam P Butler
  17. Jon W Teague
  18. George S Vassiliou
  19. Anthony R Green
  20. Ming-Qing Du
  21. Ashwin Unnikrishnan
  22. John E Pimanda
  23. Bin Tean Teh
  24. Nikhil Munshi
  25. Mel Greaves
  26. Paresh Vyas
  27. Adel K El-Naggar
  28. Tom Santarius
  29. V Peter Collins
  30. Richard Grundy
  31. Jack A Taylor
  32. D Neil Hayes
  33. David Malkin
  34. ICGC Breast Cancer Group
  35. ICGC Chronic Myeloid Disorders Group
  36. ICGC Prostate Cancer Group
  37. Christopher S Foster
  38. Anne Y Warren
  39. Hayley C Whitaker
  40. Daniel Brewer
  41. Rosalind Eeles
  42. Colin Cooper
  43. David Neal
  44. Tapio Visakorpi
  45. William B Isaacs
  46. G Steven Bova
  47. Adrienne M Flanagan
  48. P Andrew Futreal
  49. Andy G Lynch
  50. Patrick F Chinnery
  51. Ultan McDermott
  52. Michael R Stratton
  53. Peter J Campbell  Is a corresponding author
  1. Wellcome Trust Sanger Institute, United Kingdom
  2. University of Cambridge, United Kingdom
  3. Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  4. University of New South Wales, Australia
  5. National Cancer Centre, Singapore
  6. Dana-Farber Cancer Institute, United States
  7. Institute of Cancer Research, Sutton, United Kingdom
  8. University of Oxford, United Kingdom
  9. MD Anderson Cancer Center, United States
  10. University of Nottingham, United Kingdom
  11. National Institute of Health, United States
  12. University of North Carolina, United States
  13. University of Toronto, Canada
  14. University of Liverpool, United Kingdom
  15. University of East Anglia, United Kingdom
  16. University of Tampere, Finland
  17. Johns Hopkins University, United States
  18. Royal National Orthopaedic Hospital, United Kingdom
  19. Newcastle University, United Kingdom
Research Article
  • Cited 172
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Cite this article as: eLife 2014;3:e02935 doi: 10.7554/eLife.02935
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Abstract

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.

Article and author information

Author details

  1. Young Seok Ju

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Ludmil B Alexandrov

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Moritz Gerstung

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Inigo Martincorena

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Serena Nik-Zainal

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Manasa Ramakrishna

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Helen R Davies

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Elli Papaemmanuil

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Gunes Gundem

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Adam Shlien

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Niccolo Bolli

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sam Behjati

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Patrick S Tarpey

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Jyoti Nangalia

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Charles E Massie

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Adam P Butler

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Jon W Teague

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. George S Vassiliou

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Anthony R Green

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  20. Ming-Qing Du

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Ashwin Unnikrishnan

    University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  22. John E Pimanda

    University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  23. Bin Tean Teh

    National Cancer Centre, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  24. Nikhil Munshi

    Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Mel Greaves

    Institute of Cancer Research, Sutton, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  26. Paresh Vyas

    University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  27. Adel K El-Naggar

    MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Tom Santarius

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  29. V Peter Collins

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  30. Richard Grundy

    University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  31. Jack A Taylor

    National Institute of Health, Triangle, North Carolina, United States
    Competing interests
    The authors declare that no competing interests exist.
  32. D Neil Hayes

    University of North Carolina, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  33. David Malkin

    University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  34. ICGC Breast Cancer Group

    Competing interests
    The authors declare that no competing interests exist.
  35. ICGC Chronic Myeloid Disorders Group

    Competing interests
    The authors declare that no competing interests exist.
  36. ICGC Prostate Cancer Group

    Competing interests
    The authors declare that no competing interests exist.
  37. Christopher S Foster

    University of Liverpool, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  38. Anne Y Warren

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  39. Hayley C Whitaker

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  40. Daniel Brewer

    University of East Anglia, Norwich, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  41. Rosalind Eeles

    Institute of Cancer Research, Sutton, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  42. Colin Cooper

    Institute of Cancer Research, Sutton, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  43. David Neal

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  44. Tapio Visakorpi

    University of Tampere, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  45. William B Isaacs

    Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  46. G Steven Bova

    University of Tampere, Tampere, Finland
    Competing interests
    The authors declare that no competing interests exist.
  47. Adrienne M Flanagan

    Royal National Orthopaedic Hospital, Middlesex, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  48. P Andrew Futreal

    MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  49. Andy G Lynch

    University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  50. Patrick F Chinnery

    Newcastle University, Newcastle-upon-tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  51. Ultan McDermott

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  52. Michael R Stratton

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  53. Peter J Campbell

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    For correspondence
    pc8@sanger.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: We obtained informed consent and consent to publish from participants enrolled in this study.Ethical approval references:Genome Analysis of myeloid and lymphoid malignancies (10/H0306/40)Genomic Analysis of Mesothelioma (11/EE/0444)Myeloid and lymphoid cancer genome analysis (07/S1402/90)The Treatment of Down Syndrome Children with Acute Myeloid Leukemia and Myelodysplastic Syndrome(AAML0431)CLL (chronic lymphocytic leukaemia) genome analysis (07/Q0104/3)CGP-Exome sequencing of Down syndrome associated acute myeloid leukemia samples (IRB 13-010133)Cancer Genome Project - Global approaches to characterising the molecular basis of paediatric ependymoma (05/MRE04/70)PREDICT-Cohort (09/H0801/96)ICGC Prostate (Evaluation of biomarkers in urological diseases) (LREC 03/018)ICGC Prostate (779) (Prostate Complex CRUK Sample Cohort) (MREC/01/4/061)ICGC Prostate (Tissue collection at radical prostatectomy) (CRE-2011.373)Somatic molecular genetics of human cancers, melanoma and myeloma (Dana Farber Cancer Institute)(08/H0308/303)Breast Cancer Genome Analysis for the International Cancer Genome Consortium Working Group (09/H0306/36)Genome analysis of tumours of the bone (09/H0308/165)

Reviewing Editor

  1. Todd Golub, Broad Institute, United States

Publication history

  1. Received: March 28, 2014
  2. Accepted: September 26, 2014
  3. Accepted Manuscript published: October 1, 2014 (version 1)
  4. Version of Record published: November 4, 2014 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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