# Geographic and age variations in mutational processes in colorectal cancer

Source: https://onco.cc/key-papers/paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025/  
OnCo record `paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading 981 bowel cancer genomes from 11 countries found that the fingerprint of colibactin, a DNA-damaging toxin made by some gut bacteria, is more than three times as common in people diagnosed under 40 as over 70, and is stamped on the tumour early in life. It is the strongest lead yet on why bowel cancer is rising in young adults.

## Summary

Díaz-Gay, Dos Santos, Moody and colleagues examined 981 colorectal cancer genomes from 11 countries to ask whether mutational processes contribute to geographic and age-related differences in incidence. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases.

Multiple signatures, most with unknown aetiologies, varied in prevalence across Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates, were enriched in early-onset cancers and were imprinted early during tumour development. Colibactin exposure was further linked to APC driver mutations.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: Nature
- Year: 2025
- DOI: 10.1038/s41586-025-09025-8
- Authors: Díaz-Gay M, Dos Santos W, Moody S, et al.
- Findings: 981 genomes from 11 countries; 802 microsatellite-stable cases carried the geographic and age variation.; Colibactin signatures SBS88 and ID18 were 3.3 times more common in people diagnosed before 40 than in those over 70.; SBS88 and ID18 mutation loads were higher in countries with higher colorectal cancer incidence.; ID18 was responsible for about 25 percent of APC driver insertions and deletions in colibactin-positive cases.; The colibactin signatures were imprinted early during colorectal cancer development.
- What it means: If a childhood exposure to colibactin-producing Escherichia coli writes APC mutations into the colon decades before a tumour appears, then the rise in early-onset bowel cancer may be preventable by something done in childhood rather than by screening alone.
- Caveats: Association, not causation: the signature records exposure at some point, and no trial has shown that removing colibactin-producing bacteria lowers risk.; 981 genomes across 11 countries is a thin sample per country, and the countries were not chosen to be representative.; Most of the geographically variable signatures still have no known cause.

## Sources

- Nature 2025: https://doi.org/10.1038/s41586-025-09025-8
- PubMed: https://pubmed.ncbi.nlm.nih.gov/40267983/
- Europe PMC full text (PMC12221974): https://europepmc.org/article/MED/40267983

## Connected records

- key papers: [Colorectal cancer incidence patterns in the United States, 1974-2013](https://onco.cc/key-papers/paper-siegel-colorectal-incidence-birth-cohort-jnci-2017/), [Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years](https://onco.cc/key-papers/paper-vuik-early-onset-colorectal-europe-gut-2019/), [Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women](https://onco.cc/key-papers/paper-hur-sugar-sweetened-beverages-early-onset-colorectal-gut-2021/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Early-onset colorectal cancer (under 50)](https://onco.cc/cancers/early-onset-colorectal/)
- fronts: [Prevention & Risk](https://onco.cc/fronts/prevention/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [APC](https://onco.cc/targets/apc/)
- institutions: [International Agency for Research on Cancer (IARC / WHO)](https://onco.cc/institutions/iarc/)
- pathways: [Microbiome-tumour interactions](https://onco.cc/pathways/microbiome-tumour/)
- terms: [Gut microbiome diversity and composition](https://onco.cc/terms/gut-microbiome-diversity/)
- bottlenecks: [Metastasis is understood least and studied last](https://onco.cc/bottlenecks/b-metastasis-biology/), [Prevention we already have is not deployed](https://onco.cc/bottlenecks/b-prevention-adoption/), [The hardest cancers are found late](https://onco.cc/bottlenecks/b-early-detection/)
- journals: [Nature](https://onco.cc/journals/nature/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)
- ideas: [Find out what is driving early-onset bowel cancer, starting with colibactin, before extending screening any further](https://onco.cc/ideas/idea-crc-early-onset-cause-hunt/)

---
JSON: https://onco.cc/api/v1/entities/paper-diaz-gay-colibactin-geographic-age-mutational-processes-nature-2025.json