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Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

Ju, Young Seok, Alexandrov, Ludmil B, Gerstung, Moritz, Martincorena, Inigo, Nik-Zainal, Serena, Ramakrishna, Manasa, Davies, Helen R, Papaemmanuil, Elli, Gundem, Gunes, Shlien, Adam, Bolli, Niccolo, Behjati, Sam, Tarpey, Patrick S, Nangalia, Jyoti, Massie, Charles E, Butler, Adam P, Teague, Jon W, Vassiliou, George S, Green, Anthony R, Du, Ming-Qing, Unnikrishnan, Ashwin, Pimanda, John E, Teh, Bin Tean, Munshi, Nikhil, Greaves, Mel, Vyas, Paresh, El-Naggar, Adel K, Santarius, Tom, Collins, V Peter, Grundy, Richard, Taylor, Jack A, Hayes, D Neil, Malkin, David, ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Foster, Christopher S, Warren, Anne Y, Whitaker, Hayley C, Brewer, Daniel, Eeles, Rosalind, Cooper, Colin, Neal, David, Visakorpi, Tapio, Isaacs, William B, Bova, G Steven, Flanagan, Adrienne M, Futreal, P Andrew, Lynch, Andy G, Chinnery, Patrick F, McDermott, Ultan, Stratton, Michael R, Campbell, Peter J·2014·eLife
DOI 10.7554/elife.02935PMC PMC4371858
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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. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 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. A number 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.

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  • The mutational spectra of filtered somatic mtDNA substitutions across species were broadly consistent with those previously observed in studies of human tissues, with a dominance of C>T and T>C transversions and a strong replication strand bias.

    “The specificity of the filtered variant calls was supported by the observation that the mutational spectra across species were broadly consistent with those previously observed in studies of human tissues46, with a dominance of C>T and T>C transversions and a strong replication strand bias.”

    From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [46]

    The Results section, ‘Extracting mtDNA mutational signatures,’ says C>T and T>C are transitions, not transversions, and reports a strong strand bias. It describes human cancer mtDNA and consistency across tumor types, not mutational spectra across species. (LLM, conf=0.88)

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  • The mutational spectra across species appeared broadly consistent with that observed in humans, with a dominance of C>T and A>G substitutions believed to result from mtDNA replication errors rather than DNA damage.

    “The mutational spectra across species appeared broadly consistent with that observed in humans, with a dominance of C>T and A>G substitutions that are believed to result from mitochondrial DNA (mtDNA) replication errors rather than DNA damage46 (Extended Data Fig. 14b).”

    From Somatic mutation rates scale with lifespan across mammals (2022) · cites this paper as [46]

    The Results section reports that C>T and T>C dominate the human cancer mtDNA substitutions; an analysis of codon usage in seven animal species suggests a similar mutational pressure in vertebrates, particularly primates. The Discussion proposes replication-coupled mechanisms, including polymerase errors with a C>T and A>G pattern, and argues against reactive oxygen species as the cause. It does not establish broadly consistent mutational spectra across species or identify replication errors, rather than DNA damage generally, as the cause. (LLM, conf=0.85)

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Metadata

Authors
Ju, Y. S., Alexandrov, L. B., Gerstung, M., Martincorena, I., Nik-Zainal, S., Ramakrishna, M., Davies, H. R., Papaemmanuil, E., Gundem, G., Shlien, A., Bolli, N., Behjati, S., Tarpey, P. S., Nangalia, J., Massie, C. E., Butler, A. P., Teague, J. W., Vassiliou, G. S., Green, A. R., Du, M.-Q., Unnikrishnan, A., Pimanda, J. E., Teh, B. T., Munshi, N., Greaves, M., Vyas, P., El-Naggar, A. K., Santarius, T., Collins, V. P., Grundy, R., Taylor, J. A., Hayes, D. N., Malkin, D., ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Foster, C. S., Warren, A. Y., Whitaker, H. C., Brewer, D., Eeles, R., Cooper, C., Neal, D., Visakorpi, T., Isaacs, W. B., Bova, G. S., Flanagan, A. M., Futreal, P. A., Lynch, A. G., Chinnery, P. F., McDermott, U., Stratton, M. R., & Campbell, P. J.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2014-10-01
Volume
3
ISSN
2050-084X
DOI
10.7554/elife.02935
PMC
PMC4371858
Cited by
355
References
10
Language
en
Licence
Funders
  • Wellcome Trust (Health Innovation Challenge Fund (HICF))
  • Kay Kendall Leukaemia Fund
  • Chordoma Foundation
  • Adenoid Cystic Carcinoma Research Foundation
  • European Molecular Biology Organization (ALTF 1203_2012, ALTF 1287-2012)
  • National Institute for Health Research (Biomedical Research Center at University College London Hospitals, Cambridge Biomedical Research Center)
  • Leukaemia and Lymphoma Research
  • Cancer Research UK
  • Leukemia and Lymphoma Society
  • European Union (Breast Cancer Somatic Genetics Study (BASIS))
  • National Cancer Research Institute (PROMPT: G0500966/75466)
  • National Institute of Environmental Health Sciences (Intramural Research Program of the NIH)
  • Department of Health (Health Innovation Challenge Fund (HICF))

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