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

Nature. 2020 Apr;580(7802):269-273. doi: 10.1038/s41586-020-2080-8. Epub 2020 Feb 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Peptides
  • Polyketides
  • colibactin