Journal Article

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

Clevers, Hans, Top, Janetta, Paganelli, Fernanda L., van Boxtel, Ruben, Puschhof, Jens, Gurjao, Carino, Stege, Paul B., Bonnet, Richard, Miao, Yi, Garcia, K. Christopher, Pleguezuelos-Manzano, Cayetano, Willems, Rob J. L., Nomburg, Jason, Geurts, Maarten H., van Hoeck, Arne, Mizutani, Tomohiro, Dalmasso, Guillaume, Rosendahl Huber, Axel, van der Linden, Reinier, Giannakis, Marios, Meyerson, Matthew, Manders, Freek, Quirke, Phil, van der Elst, Stefan, Cuppen, Edwin, Wood, Henry M., Beumer, Joep

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/100 / 13/106 / 45 / 45/23 / 631/326/421 / 631/532/2437 / 631/67/327 / 631/67/68 / 631/67/70 / Adenine / Alkylation / Bacteria / Bacteriology / Biochemistry, Molecular Biology / Cancer / Coculture Techniques / Cohort Studies / Colorectal cancer / 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 / Humanities and Social Sciences / Humans / Intestinal microflora / Intestine / Life Sciences / Metastasis / Microbiology and Parasitology / Microbiota / Molecular biology / multidisciplinary / Mutagenesis / Mutation / Organoids / Organoids - cytology / Organoids - metabolism / Organoids - microbiology / Pathogenicity / Pathogens / Peptides - genetics / Polyketides / Science / Science (multidisciplinary) / Signatures / Tumors / Whole genome sequencing