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Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

Author

Listed:
  • Cayetano Pleguezuelos-Manzano

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Oncode Institute)

  • Jens Puschhof

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Oncode Institute)

  • Axel Rosendahl Huber

    (Oncode Institute
    The Princess Máxima Center for Pediatric Oncology)

  • Arne van Hoeck

    (Oncode Institute
    University Medical Centre Utrecht)

  • Henry M. Wood

    (University of Leeds)

  • Jason Nomburg

    (Division of Medical Sciences, Harvard Medical School
    Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Carino Gurjao

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Freek Manders

    (Oncode Institute
    The Princess Máxima Center for Pediatric Oncology)

  • Guillaume Dalmasso

    (University Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH)

  • Paul B. Stege

    (University Medical Center Utrecht)

  • Fernanda L. Paganelli

    (University Medical Center Utrecht)

  • Maarten H. Geurts

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Oncode Institute)

  • Joep Beumer

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht)

  • Tomohiro Mizutani

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Oncode Institute)

  • Yi Miao

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Reinier van der Linden

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht)

  • Stefan van der Elst

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht)

  • K. Christopher Garcia

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Janetta Top

    (University Medical Center Utrecht)

  • Rob J. L. Willems

    (University Medical Center Utrecht)

  • Marios Giannakis

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Richard Bonnet

    (University Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH
    University Hospital of Clermont-Ferrand)

  • Phil Quirke

    (University of Leeds)

  • Matthew Meyerson

    (Dana-Farber Cancer Institute and Harvard Medical School
    Broad Institute of MIT and Harvard
    Harvard Medical School
    Harvard Medical School)

  • Edwin Cuppen

    (Oncode Institute
    University Medical Centre Utrecht
    Hartwig Medical Foundation
    CPCT Consortium)

  • Ruben van Boxtel

    (Oncode Institute
    The Princess Máxima Center for Pediatric Oncology)

  • Hans Clevers

    (Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
    Oncode Institute
    The Princess Máxima Center for Pediatric Oncology)

Abstract

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

Suggested Citation

  • Cayetano Pleguezuelos-Manzano & Jens Puschhof & Axel Rosendahl Huber & Arne van Hoeck & Henry M. Wood & Jason Nomburg & Carino Gurjao & Freek Manders & Guillaume Dalmasso & Paul B. Stege & Fernanda L., 2020. "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli," Nature, Nature, vol. 580(7802), pages 269-273, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7802:d:10.1038_s41586-020-2080-8
    DOI: 10.1038/s41586-020-2080-8
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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. Carmen Aguilar & Mindaugas Pauzuolis & Malvika Pompaiah & Ehsan Vafadarnejad & Panagiota Arampatzi & Mara Fischer & Dominik Narres & Mastura Neyazi & Özge Kayisoglu & Thomas Sell & Nils Blüthgen & Mar, 2022. "Helicobacter pylori shows tropism to gastric differentiated pit cells dependent on urea chemotaxis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. 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.
    4. Huiyuan Zhu & Man Li & Dexi Bi & Huiqiong Yang & Yaohui Gao & Feifei Song & Jiayi Zheng & Ruting Xie & Youhua Zhang & Hu Liu & Xuebing Yan & Cheng Kong & Yefei Zhu & Qian Xu & Qing Wei & Huanlong Qin, 2024. "Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Candice R. Gurbatri & Georgette A. Radford & Laura Vrbanac & Jongwon Im & Elaine M. Thomas & Courtney Coker & Samuel R. Taylor & YoungUk Jang & Ayelet Sivan & Kyu Rhee & Anas A. Saleh & Tiffany Chien , 2024. "Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Lulu Sun & Yi Zhang & Jie Cai & Bipin Rimal & Edson R. Rocha & James P. Coleman & Chenran Zhang & Robert G. Nichols & Yuhong Luo & Bora Kim & Yaozong Chen & Kristopher W. Krausz & Curtis C. Harris & A, 2023. "Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Francesca Menghi & Edison T. Liu, 2022. "Functional genomics of complex cancer genomes," Nature Communications, Nature, vol. 13(1), pages 1-4, December.
    8. 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.
    9. Sujath Abbas & Oriol Pich & Ginny Devonshire & Shahriar A. Zamani & Annalise Katz-Summercorn & Sarah Killcoyne & Calvin Cheah & Barbara Nutzinger & Nicola Grehan & Nuria Lopez-Bigas & Rebecca C. Fitzg, 2023. "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Wanting Dong & Xinyue Fan & Yaqiong Guo & Siyi Wang & Shulei Jia & Na Lv & Tao Yuan & Yuanlong Pan & Yong Xue & Xi Chen & Qian Xiong & Ruifu Yang & Weigang Zhao & Baoli Zhu, 2024. "An expanded database and analytical toolkit for identifying bacterial virulence factors and their associations with chronic diseases," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. 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.
    12. 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.

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