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Various species of the intestinal microbiota have been associated with the development of colorectal cancer (CRC)1,2, yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. 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 a period of 5 months. Whole-genome sequencing of clonal organoids before and after this exposure reveals a distinct mutational signature, absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature is detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in CRC. Our study describes a distinct mutational signature in CRC and implies that the underlying mutational process directly results from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
Cayetano Pleguezuelos-Manzano,Jens Puschhof,Axel Rosendahl Huber
Ruben van Boxtel,Hans Clevers
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,Reinier van der Linden,Stefan van Elst,Genomics England Research Consortium,Janetta Top,Rob J L Willems,Marios Giannakis,Richard Bonnet,Phil Quirke,Matthew Meyerson,Edwin Cuppen,Ruben van Boxtel,Hans Clevers