Contribution of pks+ E. coli mutations to colorectal carcinogenesis

Bingjie Chen, Daniele Ramazzotti, Timon Heide, Inmaculada Spiteri, Javier Fernandez-Mateos, Chela James, Luca Magnani, Trevor A. Graham (trevor.graham@icr.ac.uk) and Andrea Sottoriva (andrea.sottoriva@fht.org)
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Bingjie Chen: The Institute of Cancer Research
Daniele Ramazzotti: University of Milano-Bicocca
Timon Heide: The Institute of Cancer Research
Inmaculada Spiteri: The Institute of Cancer Research
Javier Fernandez-Mateos: The Institute of Cancer Research
Chela James: The Institute of Cancer Research
Luca Magnani: The Institute of Cancer Research
Trevor A. Graham: The Institute of Cancer Research
Andrea Sottoriva: The Institute of Cancer Research

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43329-5

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