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

Autor: Arne Van Hoeck, Jens Puschhof, Axel Rosendahl Huber, Ruben van Boxtel, Reinier van der Linden, Fernanda L. Paganelli, K. Christopher Garcia, Stefan van der Elst, Matthew Meyerson, Hans Clevers, Guillaume Dalmasso, Marios Giannakis, Richard Bonnet, Paul B. Stege, Phil Quirke, Tomohiro Mizutani, Henry M. Wood, Edwin Cuppen, Rob J. L. Willems, Maarten H. Geurts, Carino Gurjao, Cayetano Pleguezuelos-Manzano, Joep Beumer, Freek Manders, Yi Miao, Janetta Top, Jason Nomburg
Přispěvatelé: Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), National Institute for Health Research (NIHR) NHS England Wellcome Trust Cancer Research UK Medical Research Council UK (MRC) CRUK grant OPTIMISTICC C10674/A27140Gravitation projects CancerGenomiCs.nl Netherlands Organ-on-Chip Initiative from the Netherlands Organisation for Scientific Research (NWO) - Ministry of Education, Culture and Science of the government of the Netherlands 024.003.001Oncode Institute - Dutch Cancer Society European Research Council under ERC Advanced Grant 67013VIDI grant from the NWO 016.Vidi.171.023NWO building blocks of life project: Cell dynamics within lung and intestinal organoids 737.016.009ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Sante, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan HTE201601Howard Hughes Medical Institute Mathers Foundation United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA1R01DK115728-01A1, Hubrecht Institute for Developmental Biology and Stem Cell Research
Rok vydání: 2020
Předmět:
Zdroj: Nature
Nature, Nature Publishing Group, 2020, 580 (7802), pp.269-273. ⟨10.1038/s41586-020-2080-8⟩
Nature, 580(7802), 269-273. Nature Publishing Group
ISSN: 1476-4687
0028-0836
1476-4679
DOI: 10.1038/s41586-020-2080-8
Popis: International audience; Various species of the intestinal microbiota have been associated with the development of colorectal cancer(1,2), 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 colibactin(3). This compound is believed to alkylate DNA on adenine residues(4,5) and induces double-strand breaks in cultured cells(3). 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.Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks(+) island develop a distinct mutational signature associated with colorectal cancer.
Databáze: OpenAIRE
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