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The landscape of somatic mutation in normal colorectal epithelial cells

Author

Listed:
  • Henry Lee-Six

    (Wellcome Sanger Institute)

  • Sigurgeir Olafsson

    (Wellcome Sanger Institute)

  • Peter Ellis

    (Wellcome Sanger Institute)

  • Robert J. Osborne

    (Wellcome Sanger Institute)

  • Mathijs A. Sanders

    (Wellcome Sanger Institute
    Erasmus University Medical Center)

  • Luiza Moore

    (Wellcome Sanger Institute)

  • Nikitas Georgakopoulos

    (University of Cambridge
    Cambridge Biomedical Campus)

  • Franco Torrente

    (Addenbrooke’s Hospital)

  • Ayesha Noorani

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Martin Goddard

    (Papworth Hospital NHS Trust)

  • Philip Robinson

    (Wellcome Sanger Institute)

  • Tim H. H. Coorens

    (Wellcome Sanger Institute)

  • Laura O’Neill

    (Wellcome Sanger Institute)

  • Christopher Alder

    (Wellcome Sanger Institute)

  • Jingwei Wang

    (Wellcome Sanger Institute)

  • Rebecca C. Fitzgerald

    (University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Matthias Zilbauer

    (Addenbrooke’s Hospital
    University of Cambridge)

  • Nicholas Coleman

    (Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

  • Kourosh Saeb-Parsy

    (University of Cambridge
    Cambridge Biomedical Campus)

  • Inigo Martincorena

    (Wellcome Sanger Institute)

  • Peter J. Campbell

    (Wellcome Sanger Institute)

  • Michael R. Stratton

    (Wellcome Sanger Institute)

Abstract

The colorectal adenoma–carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes—which may occur in morphologically normal tissue—is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.

Suggested Citation

  • Henry Lee-Six & Sigurgeir Olafsson & Peter Ellis & Robert J. Osborne & Mathijs A. Sanders & Luiza Moore & Nikitas Georgakopoulos & Franco Torrente & Ayesha Noorani & Martin Goddard & Philip Robinson &, 2019. "The landscape of somatic mutation in normal colorectal epithelial cells," Nature, Nature, vol. 574(7779), pages 532-537, October.
    • Handle: RePEc:nat:nature:v:574:y:2019:i:7779:d:10.1038_s41586-019-1672-7
    DOI: 10.1038/s41586-019-1672-7
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    Citations

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    Cited by:

    1. Bingjie Chen & Daniele Ramazzotti & Timon Heide & Inmaculada Spiteri & Javier Fernandez-Mateos & Chela James & Luca Magnani & Trevor A. Graham & Andrea Sottoriva, 2023. "Contribution of pks+ E. coli mutations to colorectal carcinogenesis," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. 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.
    3. Thomas G. Paulson & Patricia C. Galipeau & Kenji M. Oman & Carissa A. Sanchez & Mary K. Kuhner & Lucian P. Smith & Kevin Hadi & Minita Shah & Kanika Arora & Jennifer Shelton & Molly Johnson & Andre Co, 2022. "Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. 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.
    5. Kitty Sherwood & Joseph C. Ward & Ignacio Soriano & Lynn Martin & Archie Campbell & Raheleh Rahbari & Ioannis Kafetzopoulos & Duncan Sproul & Andrew Green & Julian R. Sampson & Alan Donaldson & Kai-Re, 2023. "Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    6. Bernard C. H. Lee & Philip S. Robinson & Tim H. H. Coorens & Helen H. N. Yan & Sigurgeir Olafsson & Henry Lee-Six & Mathijs A. Sanders & Hoi Cheong Siu & James Hewinson & Sarah S. K. Yue & Wai Yin Tsu, 2022. "Mutational landscape of normal epithelial cells in Lynch Syndrome patients," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. 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.
    8. 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.
    9. Luan Nguyen & Arne Hoeck & Edwin Cuppen, 2022. "Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. 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.
    11. 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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