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Tobacco smoking and somatic mutations in human bronchial epithelium

Author

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  • Kenichi Yoshida

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Kate H. C. Gowers

    (University College London)

  • Henry Lee-Six

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Deepak P. Chandrasekharan

    (University College London)

  • Tim Coorens

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Elizabeth F. Maughan

    (University College London)

  • Kathryn Beal

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Andrew Menzies

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Fraser R. Millar

    (University College London)

  • Elizabeth Anderson

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Sarah E. Clarke

    (University College London)

  • Adam Pennycuick

    (University College London)

  • Ricky M. Thakrar

    (University College London
    University College London Hospital)

  • Colin R. Butler

    (University College London
    University College London Hospital)

  • Nobuyuki Kakiuchi

    (Kyoto University)

  • Tomonori Hirano

    (Kyoto University)

  • Robert E. Hynds

    (University College London
    CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London)

  • Michael R. Stratton

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Iñigo Martincorena

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Sam M. Janes

    (University College London
    University College London Hospital)

  • Peter J. Campbell

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    Stem Cell Institute, University of Cambridge)

Abstract

Tobacco smoking causes lung cancer1–3, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA4,5. The profound effects of tobacco on the genome of lung cancer cells are well-documented6–10, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4–14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0–6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

Suggested Citation

  • Kenichi Yoshida & Kate H. C. Gowers & Henry Lee-Six & Deepak P. Chandrasekharan & Tim Coorens & Elizabeth F. Maughan & Kathryn Beal & Andrew Menzies & Fraser R. Millar & Elizabeth Anderson & Sarah E. , 2020. "Tobacco smoking and somatic mutations in human bronchial epithelium," Nature, Nature, vol. 578(7794), pages 266-272, February.
  • Handle: RePEc:nat:nature:v:578:y:2020:i:7794:d:10.1038_s41586-020-1961-1
    DOI: 10.1038/s41586-020-1961-1
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    Citations

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    Cited by:

    1. Ewart Kuijk & Onno Kranenburg & Edwin Cuppen & Arne Van Hoeck, 2022. "Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Sriram Vijayraghavan & Thomas Blouin & James McCollum & Latarsha Porcher & François Virard & Jiri Zavadil & Carol Feghali-Bostwick & Natalie Saini, 2024. "Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Kasumi Murai & Stefan Dentro & Swee Hoe Ong & Roshan Sood & David Fernandez-Antoran & Albert Herms & Vasiliki Kostiou & Irina Abnizova & Benjamin A. Hall & Moritz Gerstung & Philip H. Jones, 2022. "p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Biancastella Cereser & Angela Yiu & Neha Tabassum & Lisa Del Bel Belluz & Sladjana Zagorac & Kenneth Russell Zapanta Ancheta & Rongrong Zhong & Cristian Miere & Alicia Rose Jeffries-Jones & Nina Moder, 2023. "The mutational landscape of the adult healthy parous and nulliparous human breast," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Manako Yamaguchi & Hirofumi Nakaoka & Kazuaki Suda & Kosuke Yoshihara & Tatsuya Ishiguro & Nozomi Yachida & Kyota Saito & Haruka Ueda & Kentaro Sugino & Yutaro Mori & Kaoru Yamawaki & Ryo Tamura & Sun, 2022. "Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Philip S. Robinson & Laura E. Thomas & Federico Abascal & Hyunchul Jung & Luke M. R. Harvey & Hannah D. West & Sigurgeir Olafsson & Bernard C. H. Lee & Tim H. H. Coorens & Henry Lee-Six & Laura Butlin, 2022. "Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Jonathan C. M. Wan & Dennis Stephens & Lingqi Luo & James R. White & Caitlin M. Stewart & Benoît Rousseau & Dana W. Y. Tsui & Luis A. Diaz, 2022. "Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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