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

Genomics England Research Consortium

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

573 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)269-273
Aantal pagina's5
TijdschriftNature
Volume580
Nummer van het tijdschrift7802
DOI's
StatusGepubliceerd - apr. 2020

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