Colibactin DNA-damage signature indicates mutational impact in colorectal cancer

Nat Med. 2020 Jul;26(7):1063-1069. doi: 10.1038/s41591-020-0908-2. Epub 2020 Jun 1.

Abstract

The mucosal epithelium is a common target of damage by chronic bacterial infections and the accompanying toxins, and most cancers originate from this tissue. We investigated whether colibactin, a potent genotoxin1 associated with certain strains of Escherichia coli2, creates a specific DNA-damage signature in infected human colorectal cells. Notably, the genomic contexts of colibactin-induced DNA double-strand breaks were enriched for an AT-rich hexameric sequence motif, associated with distinct DNA-shape characteristics. A survey of somatic mutations at colibactin target sites of several thousand cancer genomes revealed notable enrichment of this motif in colorectal cancers. Moreover, the exact double-strand-break loci corresponded with mutational hot spots in cancer genomes, reminiscent of a trinucleotide signature previously identified in healthy colorectal epithelial cells3. The present study provides evidence for the etiological role of colibactin in human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / microbiology
  • Colorectal Neoplasms / pathology
  • DNA Breaks, Double-Stranded / drug effects*
  • DNA Damage / drug effects*
  • Epithelial Cells / drug effects
  • Escherichia coli / pathogenicity
  • Humans
  • Mutation / drug effects
  • Nucleotide Motifs / drug effects
  • Peptides / pharmacology*
  • Polyketides / pharmacology*

Substances

  • Peptides
  • Polyketides
  • colibactin