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; Hans Clevers

doi:10.1038/s41586-020-2080-8

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 WillemsMarios Giannakis, Richard Bonnet, Phil Quirke, Matthew Meyerson, Edwin Cuppen, Ruben van Boxtel, Hans Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

737 Citations (Scopus)

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.

Original language	English
Pages (from-to)	269-273
Number of pages	5
Journal	Nature
Volume	580
Issue number	7802
DOIs	https://doi.org/10.1038/s41586-020-2080-8
Publication status	Published - Apr 2020

Keywords

Coculture Techniques
Cohort Studies
Colorectal Neoplasms/genetics
Consensus Sequence
DNA Damage
Escherichia coli/genetics
Gastrointestinal Microbiome
Genomic Islands/genetics
Humans
Mutagenesis
Mutation
Organoids/cytology
Peptides/genetics
Polyketides

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Pleguezuelos-Manzano, C., Puschhof, J., Rosendahl Huber, A., van Hoeck, A., Wood, H. M., Nomburg, J., Gurjao, C., Manders, F., Dalmasso, G., Stege, P. B., Paganelli, F. L., Geurts, M. H., Beumer, J., Mizutani, T., Miao, Y., van der Linden, R., van der Elst, S., Garcia, K. C., Top, J., ... Clevers, H. (2020). Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature, 580(7802), 269-273. https://doi.org/10.1038/s41586-020-2080-8

@article{ee7dd56a51e143468ca5ade452d7c9f0,

title = "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli",

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.",

keywords = "Coculture Techniques, Cohort Studies, Colorectal Neoplasms/genetics, Consensus Sequence, DNA Damage, Escherichia coli/genetics, Gastrointestinal Microbiome, Genomic Islands/genetics, Humans, Mutagenesis, Mutation, Organoids/cytology, Peptides/genetics, Polyketides",

author = "Cayetano Pleguezuelos-Manzano and Jens Puschhof and {Rosendahl Huber}, Axel and {van Hoeck}, Arne and Wood, {Henry M} and Jason Nomburg and Carino Gurjao and Freek Manders and Guillaume Dalmasso and Stege, {Paul B} and Paganelli, {Fernanda L} and Geurts, {Maarten H} and Joep Beumer and Tomohiro Mizutani and Yi Miao and {van der Linden}, Reinier and {van der Elst}, Stefan and Garcia, {K Christopher} and Janetta Top and Willems, {Rob J L} and Marios Giannakis and Richard Bonnet and Phil Quirke and Matthew Meyerson and Edwin Cuppen and {van Boxtel}, Ruben and Hans Clevers",

year = "2020",

month = apr,

doi = "10.1038/s41586-020-2080-8",

language = "English",

volume = "580",

pages = "269--273",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7802",

}

Pleguezuelos-Manzano, C, Puschhof, J, Rosendahl Huber, A, van Hoeck, A, Wood, HM, Nomburg, J, Gurjao, C, Manders, F, Dalmasso, G, Stege, PB, Paganelli, FL, Geurts, MH, Beumer, J, Mizutani, T, Miao, Y, van der Linden, R, van der Elst, S, Garcia, KC, Top, J, Willems, RJL, Giannakis, M, Bonnet, R, Quirke, P, Meyerson, M, Cuppen, E, van Boxtel, R & Clevers, H 2020, 'Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli', Nature, vol. 580, no. 7802, pp. 269-273. https://doi.org/10.1038/s41586-020-2080-8

TY - JOUR

T1 - Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

AU - Pleguezuelos-Manzano, Cayetano

AU - Puschhof, Jens

AU - Rosendahl Huber, Axel

AU - van Hoeck, Arne

AU - Wood, Henry M

AU - Nomburg, Jason

AU - Gurjao, Carino

AU - Manders, Freek

AU - Dalmasso, Guillaume

AU - Stege, Paul B

AU - Paganelli, Fernanda L

AU - Geurts, Maarten H

AU - Beumer, Joep

AU - Mizutani, Tomohiro

AU - Miao, Yi

AU - van der Linden, Reinier

AU - van der Elst, Stefan

AU - Garcia, K Christopher

AU - Top, Janetta

AU - Willems, Rob J L

AU - Giannakis, Marios

AU - Bonnet, Richard

AU - Quirke, Phil

AU - Meyerson, Matthew

AU - Cuppen, Edwin

AU - van Boxtel, Ruben

AU - Clevers, Hans

PY - 2020/4

Y1 - 2020/4

N2 - 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.

AB - 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.

KW - Coculture Techniques

KW - Cohort Studies

KW - Colorectal Neoplasms/genetics

KW - Consensus Sequence

KW - DNA Damage

KW - Escherichia coli/genetics

KW - Gastrointestinal Microbiome

KW - Genomic Islands/genetics

KW - Humans

KW - Mutagenesis

KW - Mutation

KW - Organoids/cytology

KW - Peptides/genetics

KW - Polyketides

U2 - 10.1038/s41586-020-2080-8

DO - 10.1038/s41586-020-2080-8

M3 - Article

C2 - 32106218

SN - 0028-0836

VL - 580

SP - 269

EP - 273

JO - Nature

JF - Nature

IS - 7802

ER -

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

Abstract

Keywords

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