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

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), 2020-04, Vol.580 (7802), p.269-273 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Mutational signature in colorectal cancer caused by genotoxic pks + E. coli
Autor: 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
Assuntos: Adenine ; Alkylation ; Bacteria ; Bacteriology ; Biochemistry, Molecular Biology ; Cancer ; Coculture Techniques ; Cohort Studies ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - microbiology ; Consensus Sequence ; Datasets ; Deoxyribonucleic acid ; DNA ; DNA Damage ; E coli ; Escherichia coli ; Escherichia coli - genetics ; Escherichia coli - pathogenicity ; Exposure ; Gastrointestinal Microbiome ; Gene sequencing ; Genomes ; Genomic Islands - genetics ; Genotoxicity ; Humans ; Intestinal microflora ; Intestine ; Life Sciences ; Metastasis ; Microbiology and Parasitology ; Microbiota ; Molecular biology ; Mutagenesis ; Mutation ; Organoids ; Organoids - cytology ; Organoids - metabolism ; Organoids - microbiology ; Pathogenicity ; Pathogens ; Peptides - genetics ; Polyketides ; Signatures ; Tumors ; Whole genome sequencing
É parte de: Nature (London), 2020-04, Vol.580 (7802), p.269-273
Notas: Lead Contact
C.P.M., J.P., A.R.H. and H.C. conceived the study; C.P.M., J.P., A.R.H., R.vB. and H.C. wrote the manuscript; A.R.H, H.W, F.M. and R.vB. performed signature analysis; A.R.H., A.vH., H.W., J.N., C.G., P.Q., M.G., M.M. and E.C. provided access to and analyzed patient WGS data; G.D. and R.B. isolated bacterial strains and generated knockouts; C.P.M., J.P., T.M., R.vdL., M.H.G. and S.vE. established and performed organoid cloning experiments; C.P.M., J.P. and J.B. performed organoid co-culture experiments; P.S., F.P., J.T. and R.W. performed bacteria validation and assays.
AUTHOR CONTRIBUTION
Full author list at the end of the manuscript
Co-first author
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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