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

By Cayetano Pleguezuelos-Manzano, Jens Puschhof, Axel K M Rosendahl Huber, A. van Hoeck, H. Wood, Jason Nomburg, C. Gurjao, F. Manders, G. Dalmasso, P. Stege and 91 more. Nature, 2020

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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. 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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/c95265340401c1b0c09163e6c7c0661447247f6e

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Citations in the corpus

• The microbiome and human cancer (2021, background): “fragilis–derived toxin (22, 37, 38, 40, 41); (ii) CagA-mediated or IL-17– producing gd T cell–mediated inflammation in stomach and lung cancers, respectively (18, 103); (iii) chemoresistance through direct microbial metabolism (cytidine deaminase degradation of gemcitabine) in pancreatic cancer or i”
• Localised Colon Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. (2020, background): “Some data suggest a putative role in colon cancer carcinogenesis for factors that cause imbalances in gut microbiota.(4,5) The mortality rate in the European Union is 15e20 out of 100 000 in males and 9e14 out of 100 000 in females and has decreased over time, particularly in females.”