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

Pleguezuelos-Manzano, Puschhof, Rosendahl Huber, van Hoeck, Wood, Nomburg, Gurjao, Manders, Dalmasso, Stege, Paganelli, Geurts, Beumer, Mizutani, Miao, van der Linden, van der Elst, , Garcia, Top, Willems, Giannakis, Bonnet, Quirke, Meyerson, Cuppen, van Boxtel, Clevers (2020) Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli Nature (IF: 64.8) 580(7802) 269-273

Abstract

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, 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 colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. 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.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142898
http://www.ncbi.nlm.nih.gov/pubmed/32106218
http://dx.doi.org/10.1038/s41586-020-2080-8

Similar articles

Tools

Export to RIS