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Pleguezuelos-Manzano, Cayetano; Puschhof, Jens; Rosendahl Huber, Axel; van Hoeck, Arne; Wood, Henry M; Nomburg, Jason; Gurjao, Carino; Manders, Freek; Dalmasso, Guillaume; Stege, Paul B; Paganelli, Fernanda L; Geurts, Maarten H; Beumer, Joep; Mizutani, Tomohiro; Miao, Yi; van der Linden, Reinier; van der Elst, Stefan; Garcia, K Christopher; Top, Janetta; Willems, Rob J L; Giannakis, Marios; Bonnet, Richard; Quirke, Phil; Meyerson, Matthew; Cuppen, Edwin; van Boxtel, Ruben; Clevers, Hans
Nature (London), 04/2020, Letnik: 580, Številka: 7802Journal Article
Various species of the intestinal microbiota have been associated with the development of colorectal cancer , 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 colibactin . This compound is believed to alkylate DNA on adenine residues and induces double-strand breaks in cultured cells . 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.
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in: SICRIS
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