The rates of colorectal cancer differ by geography and have changed over time. Some areas see more cases than others. Moreover, in most countries, the number of cases in people under 50 has doubled in the past two decades. This has alarmed oncologists and researchers. Scientists do not yet fully understand what is driving this sharp increase.
Nevertheless, in an investigation by an international and multidisciplinary team of researchers led by the University of California San Diego, which explored whether mutational processes could explain these geographic and age-related differences in colorectal cancer incidence, findings revealed the role of certain gut bacteria and bacterial strains.
Study Reveals How Childhood Exposure to Colibactin May Drive Early-Onset Colorectal Cancer Epidemic
Background
Researchers examined 981 colorectal cancer genomes from 11 countries. They analyzed these genomes to identify patterns in mutations. Note that microsatellite instability or MSI is a known form of genetic mutation common in some cases of colorectal cancer. Findings showed no critical differences in MSI tumors between countries or age groups.
Microsatellites are short and repetitive DNA sequences found throughout the genome. The number of repeats can diverge between individuals. Nevertheless, following the initial findings, the researchers then focused on microsatellite-stable or MSS tumors. These tumors do not show microsatellite instability but can still harbor other mutations.
A total of 802 microsatellite-stable colorectal cancer cases were identified and investigated. The researchers found variations in mutation burden since several tumors had more mutations. There were also variations in mutational signatures. This means that different patterns of DNA changes appeared with different frequencies depending on the country.
Certain mutational signatures or specific patterns of DNA changes caused by different mutagens greatly varied by country. These differences suggest that environmental or microbial exposures to mutagens differ geographically. Countries like Argentina, Brazil, Colombia, Russia, and Thailand had unique patterns. This implied region-specific exposures.
Colibactin-Associated Signatures
Two mutational signatures, SBS88 and ID18, are caused by colibactin, a chemical produced by certain gut bacteria like several strains of Escherichia coli bacteria. These signatures were common in countries with high colorectal cancer rates. They are also much more common in early-onset colorectal cancer and in people diagnosed before age 40.
Findings specifically showed that colibactin-related mutation patterns were 3.3 times more common in colorectal cancer cases involving individuals under 40 than in those diagnosed after 70. The mutational signatures were also present in early tumor development. This indicated that the damage from colibactin likely occurred early in life.
Colibactin is toxic. It can alter DNA. Exposure in early childhood imprints a distinct genetic signature on the DNA of colon cells. This increases colorectal cancer risk before age 50. Mutations related to this bacterial toxin account for about 15 percent of APC driver mutations. APC is a tumor suppressor gene commonly mutated in colorectal cancer.
Implications
The study showed that mutational processes vary by geography and age in colorectal cancer cases while also suggesting that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer. Further details of the findings are expounded in an article published in Nature in April 2025.
Researchers fear that colorectal cancer could become the leading cause of cancer-related death among young adults by 2030 if the trend continues. Note that early-onset colorectal cancer has roughly doubled every decade for the past 20 years. This means that the number of new cases diagnosed in age groups below 50 is growing at an alarming rate.
Previous studies identified colibactin-related mutations in some colorectal cancers. However, the aforementioned study is the first to show a substantial enrichment in early-onset cases. It showed a strong case linking colibactin exposure and early-onset colorectal cancer. The researchers still cautioned that further investigation is needed to establish causality.
FURTHER READINGS AND REFERENCES
- Díaz-Gay, M., dos Santos, W., Moody, S., Kazachkova, M., Abbasi, A., Steele, C. D., Vangara, R., Senkin, S., Wang, J., Fitzgerald, S., Bergstrom, E. N., Khandekar, A., Otlu, B., Abedi-Ardekani, B., de Carvalho, A. C., Cattiaux, T., Penha, R. C. C., Gaborieau, V., Chopard, P., … Alexandrov, L. B. 2025. “Geographic and Age Variations in Mutational Processes in Colorectal Cancer.” In Nature. Springer Science and Business Media LLC. DOI: 1038/s41586-025-09025-8
- Labios, L. 23 April 2025. “Childhood Exposure to Bacterial Toxin May Be Triggering Colorectal Cancer Epidemic Among the Young.” UC San Diego Today. Regents of the University of California. Available online