Contribution of pks+ E. coli mutations to colorectal carcinogenesis
Open accessAbstract
The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.
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E. coli Nissle 1917 synthesizes and releases colibactin, a mutagenic substance that promotes colorectal polyposis and cancer and reduces cancer response to irinotecan.
“having the capability of synthetizing and releasing colibactin, a mutagenic substance described to promote colorectal polyposis and cancer, and reducing cancer response to irinotecan [26, 34–39].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [36]
The Introduction (page unavailable) describes colibactin from pks+ E. coli as genotoxic, and the Discussion (page unavailable) suggests it may contribute to colorectal carcinogenesis. The paper does not identify E. coli Nissle 1917 as the strain, establish that colibactin promotes polyposis or cancer, or address response to irinotecan. (LLM, conf=0.88)
Experimental — accuracy not yet measuredE. coli Nissle 1917 is pks-positive.
“the most widely used E. coli-based probiotic, known as E. coli Nissle 1917 (DSM 6601), is pks-positive.”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [36]
The Introduction says some E. coli strains carry the pks island, and the Results section on pks+ genomic DNA reports detecting pks genes in patient samples. Neither identifies E. coli Nissle 1917 or DSM 6601 as pks-positive; searches for Nissle, DSM 6601, and probiotic did not find a passage establishing that claim. (LLM, conf=0.76)
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- [22]Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancer caused by genotoxic pks + E. coli. Nature 1–8 10.1038/s41586-020-2080-8 (2020). PMC8142898 32106218 · DOI · Paper page
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“Colibactin produced by E. coli containing a pks island can cause double-strand breaks in mammalian DNA, promoting genome instability and increasing the mutation rate (16, 17).”
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“More broadly, an excess of colibactin-signature mutations has been observed in genes like ARID1A , TCF7L2 , TGFBR2 and other drivers in SBS88-positive tumors, especially those genes that are commonly mutated early in CRC development [19].”
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“This SBS is caused by colibactin and has been recently described to contribute to mutations in colon cancer driver genes such as APC [58].”
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Synbiotics as a Microbiome-Based Strategy in Colorectal Cancer
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“These include characteristic base substitutions and insertion–deletion mutations, providing strong molecular evidence linking pks + E. coli to human carcinogenesis [54].”
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- Authors
- Chen, B., Ramazzotti, D., Heide, T., Spiteri, I., Fernandez-Mateos, J., James, C., Magnani, L., Graham, T. A., & Sottoriva, A.
- Affiliations
- Institute of Cancer Research (GB)
- University of Milano-Bicocca (IT)
- Corresponding author
- Graham, Trevor A.
- Sottoriva, Andrea
- ORCID
- Venue
- Nature Communications
- Published
- 2023-11-29
- Volume
- 14
- Issue
- 1
- Pages
- 7827-7827
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10687070
- OpenAlex
- W4389148930
- Cited by
- 74
- References
- 24
- Citations by year
- 2026: 30 · 2025: 23 · 2024: 21
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (202778/B/16/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Screening and Detection
- Keywords
- colorectal cancer, colorectal carcinogenesis, Escherichia coli, polyketide synthase, gut microbiota, mutational signatures, DNA mismatch repair, colonic crypts, metagenomics
- MeSH terms
- Colonic Neoplasms, Escherichia coli, Humans, Mutation, Colorectal Neoplasms, Carcinogenesis
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