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  • Interpreting Colibactin-Associated Mutational Signatures and pks⁺ Bacterial Detection in Colorectal Cancer: Temporal Discordance and Biomarker Limitations

  • Mohammad Amin Noorollahian,1,* Mozhdeh Mahmoudabadi,2
    1. M.Sc. Student in Industrial Microbiology, Islamic Azad University, Mashhad
    2. M.Sc. Student in Industrial Microbiology, Islamic Azad University, Mashhad


  • Introduction: Colorectal cancer (CRC) remains a major global health burden. Recent research highlights the gut microbiome—specifically Escherichia coli strains carrying the polyketide synthase (pks) island—as a key driver of colorectal tumorigenesis. pks⁺ E. coli secretes colibactin, a genotoxin that alkylates adenine residues, creates interstrand crosslinks, and triggers double-strand DNA breaks. While these actions induce genomic instability, the connection between historical genomic scars of colibactin and the physical presence of pks⁺ bacteria in patients is not always straightforward.
  • Methods: We analyzed findings from organoid mutagenesis experiments, whole-genome sequencing of colorectal tumors and healthy colonic crypts, and microbiome profiles from tumor tissue and fecal samples across multiple cohorts to evaluate colibactin mutational signatures alongside microbial pks detection.
  • Results: Studies on human intestinal organoids show that long-term exposure to pks⁺ E. coli leaves a distinct mutational fingerprint—single-base substitutions (SBS88) and small deletions at thymine homopolymers (ID18)—which does not occur with pks-deficient strains. This signature appears in a subset of human CRCs and is notably enriched in early-onset cases. In non-cancerous colonic crypts, the colibactin signature often co-occurs with early driver mutations in APC and chromatin modifiers, pointing to an early role in tumor initiation. However, genomic footprints and bacterial presence frequently diverge. Large international cohorts of microsatellite-stable CRC show that tumor genomes bearing colibactin signatures do not consistently yield detectable pks DNA. Likewise, Japanese patient studies found no correlation between fecal clbP levels and the proportion of colibactin signatures; in fact, most tumors with high signature burdens had low clbP copy numbers.
  • Conclusion: Mutational signatures and direct bacterial detection capture different dimensions of colibactin exposure. A mutational signature records past genotoxic damage, whereas microbial testing reflects current colonization. Resolving this discrepancy will require longitudinal studies using paired tissue, mucosal, and stool samples to better evaluate colibactin as a biomarker for early CRC risk.
  • Keywords: Colorectal Cancer, pks⁺ Escherichia coli, Colibactin, Mutational Signatures (SBS88, ID18)

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