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

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. Paganelli, Maarten H. Geurts, Joep Beumer, Tomohiro Mizutani, Yi Miao, Reinier van der Linden, Stefan van der Elst, K. Christopher Garcia, Janetta Top, Rob J. L. Willems, Marios Giannakis, Richard Bonnet, Phil Quirke, Matthew Meyerson, Edwin Cuppen, Ruben van Boxtel () and Hans Clevers ()
Additional contact information
Cayetano Pleguezuelos-Manzano: Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Jens Puschhof: Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht
Axel Rosendahl Huber: Oncode Institute
Arne van Hoeck: Oncode Institute
Henry M. Wood: University of Leeds
Jason Nomburg: Division of Medical Sciences, Harvard Medical School
Carino Gurjao: Dana-Farber Cancer Institute and Harvard Medical School
Freek Manders: Oncode Institute
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
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
Yi Miao: 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
Janetta Top: University Medical Center Utrecht
Rob J. L. Willems: University Medical Center Utrecht
Marios Giannakis: Dana-Farber Cancer Institute and Harvard Medical School
Richard Bonnet: University Clermont Auvergne, Inserm U1071, INRA USC2018, M2iSH
Phil Quirke: University of Leeds
Matthew Meyerson: Dana-Farber Cancer Institute and Harvard Medical School
Edwin Cuppen: Oncode Institute
Ruben van Boxtel: Oncode Institute
Hans Clevers: Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht

Nature, 2020, vol. 580, issue 7802, 269-273

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2080-8

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