| Literature DB >> 32106218 |
Cayetano Pleguezuelos-Manzano1,2, Jens Puschhof1,2, Axel Rosendahl Huber2,3, Arne van Hoeck2,4, Henry M Wood5, Jason Nomburg6,7,8, Carino Gurjao7,8, Freek Manders2,3, Guillaume Dalmasso9, Paul B Stege10, Fernanda L Paganelli10, Maarten H Geurts1,2, Joep Beumer1, Tomohiro Mizutani1,2, Yi Miao11,12,13, Reinier van der Linden1, Stefan van der Elst1, K Christopher Garcia11,12,13, Janetta Top10, Rob J L Willems10, Marios Giannakis7,8, Richard Bonnet9,14, Phil Quirke5, Matthew Meyerson7,8,15,16, Edwin Cuppen2,4,17,18, Ruben van Boxtel19,20, Hans Clevers21,22,23.
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.Entities:
Mesh：
Substances：
Year: 2020 PMID： 32106218 PMCID： PMC8142898 DOI： 10.1038/s41586-020-2080-8
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962