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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 languageEnglish
Pages (from-to)269-273
Number of pages5
JournalNature
Volume580
Issue number7802
DOIs
Publication statusPublished - 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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