Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli
Genomics England Research Consortium
(2020) Nature, volume 580, issue 7802, pp. 269 - 273
(Article)
Abstract
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
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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.
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Keywords: Coculture Techniques, Cohort Studies, Colorectal Neoplasms/genetics, Consensus Sequence, DNA Damage, Escherichia coli/genetics, Gastrointestinal Microbiome, Genomic Islands/genetics, Humans, Mutagenesis, Mutation, Organoids/cytology, Peptides/genetics, Polyketides, General, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN: 0028-0836
Publisher: Nature Publishing Group
Note: Funding Information: Acknowledgements We thank J. H. J. Hoeijmakers, P. Knipscheer and J. I. Garaycoechea for discussions on DNA damage, and P. Robinson, K. Vervier, T. Lawley, and M. Stratton for explorative analysis and discussions. This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. This work was supported by CRUK grant OPTIMISTICC (C10674/A27140), the Gravitation projects CancerGenomiCs.nl and the Netherlands Organ-on-Chip Initiative (024.003.001) from the Netherlands Organisation for Scientific Research (NWO) funded by the Ministry of Education, Culture and Science of the government of the Netherlands (C.P.-M., J.P.), the Oncode Institute (partly financed by the Dutch Cancer Society), the European Research Council under ERC Advanced Grant Agreement no. 67013 (J.P., T.M., H.C.), a VIDI grant from the NWO (no. 016.Vidi.171.023) to R.v.B. that supports A.R.H. and NWO building blocks of life project: Cell dynamics within lung and intestinal organoids (737.016.009) (M.H.G.). With financial support from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan (HTE201601) (G.D., R.B.) as well as Howard Hughes Medical Institute, Mathers Foundation, and NIH-1R01DK115728-01A1 (Y.M., K.C.G.). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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