DNA “Time Bomb” – Common Childhood Bacteria Linked To Surge in Early-Onset Colorectal Cancer

A UC San Diego-led study linked early childhood exposure to the bacterial toxin colibactin with the rise in early-onset colorectal cancer, finding distinct DNA mutations in younger patients. The discovery points to a microbial influence on cancer risk from an early age.

An international team of researchers, led by the University of California San Diego, has identified a possible microbial factor contributing to the alarming increase in early-onset colorectal cancer: a bacterial toxin known as colibactin.

Colibactin is produced by specific strains of Escherichia coli that inhabit the colon and rectum. This toxin has the ability to damage DNA, and the new research shows that exposure to colibactin during early childhood can leave a lasting genetic “scar” on colon cells. This distinct mutation pattern may significantly raise the risk of developing colorectal cancer before the age of 50.

The study, published April 23 in Nature, examined the genomes of 981 colorectal cancer tumors from patients with both early- and late-onset disease across 11 countries with varying cancer rates. Researchers found that the DNA mutation pattern linked to colibactin was 3.3 times more common in early-onset cases, particularly among adults under the age of 40, compared to those diagnosed after age 70. These specific mutations were also more frequently observed in countries with higher rates of early-onset colorectal cancer.

“These mutation patterns are a kind of historical record in the genome, and they point to early-life exposure to colibactin as a driving force behind early-onset disease,” said study senior author Ludmil Alexandrov, professor in the Shu Chien-Gene Lay Department of Bioengineering and the Department of Cellular and Molecular Medicine at UC San Diego, who is also a member of UC San Diego Moores Cancer Center and Deputy Director of Sanford Stem Cell Fitness and Space Medicine Center.

Although previous studies—including earlier work from Alexandrov’s lab— have identified colibactin-related mutations in roughly 10 to 15 percent of all colorectal cancer cases, those studies either focused on late-onset cases or did not distinguish between early- and late-onset disease. This latest study is the first to demonstrate a substantial enrichment of colibactin-related mutations specifically in early-onset cases.

The implications are sobering. Once considered a disease of older adults, colorectal cancer is now on the rise among young people in at least 27 countries. Its incidence in adults under 50 has roughly doubled every decade for the past 20 years. If current trends continue, colorectal cancer is projected to become the leading cause of cancer-related death among young adults by 2030.

Until now, the reasons behind this surge have remained unknown. Young adults diagnosed with colorectal cancer often have no family history of the disease and few known risk factors such as obesity or hypertension. That has fueled speculation about potential hidden environmental or microbial exposures—something this new study directly investigates.

“When we started this project, we weren’t planning to focus on early-onset colorectal cancer,” said study co-first author Marcos Díaz-Gay, a former postdoctoral researcher in Alexandrov’s lab. “Our original goal was to examine global patterns of colorectal cancer to understand why some countries have much higher rates than others. But as we dug into the data, one of the most interesting and striking findings was how frequently colibactin-related mutations appeared in the early-onset cases.”

According to the team’s analysis, colibactin’s damaging effects begin early. By molecularly timing each mutational signature identified in this study, the researchers demonstrate that colibactin-associated mutations arise early in tumor development, consistent with prior studies showing that such mutations occur within the first 10 years of life. The study also reveals that colibactin-related mutations account for approximately 15% of what are known as APC driver mutations—some of the earliest genetic alterations that directly promote cancer development—in colorectal cancer.

“If someone acquires one of these driver mutations by the time they’re 10 years old,” Alexandrov explained, “they could be decades ahead of schedule for developing colorectal cancer, getting it at age 40 instead of 60.”

In other words, colibactin-producing bacteria may be silently colonizing children’s colons, initiating molecular changes in their DNA, and potentially setting the stage for colorectal cancer long before any symptoms arise.

Alexandrov cautioned that while their findings provide strong support for this hypothesis, further research is necessary to establish causality.

Building on past breakthroughs

This work—part of Cancer Grand Challenges team Mutographs, funded by Cancer Research UK—is the latest milestone in a growing body of research that Alexandrov, Díaz-Gay, and colleagues have been advancing over the past several years. Their specialty lies in decoding patterns of DNA mutations caused by environmental exposures—such as UV radiation and bacterial toxins—and lifestyle behaviors like smoking and drinking. Each factor leaves a distinct genetic fingerprint in the genome, a unique mutational signature that can help pinpoint the origins of certain cancers.

As part of a long-term collaboration between UC San Diego, the International Agency for Research on Cancer (France), and the Wellcome Sanger Institute (UK), enabled by Cancer Grand Challenges funding, team Mutographs has elucidated the mutational processes underlying esophageal, kidney, and head and neck cancers worldwide. This most recent result on colorectal cancer further expands the global understanding of cancer etiology through mutational signature analysis.

By systematically cataloging these mutational patterns across thousands of cancer genomes, the researchers have been working to identify new causes of cancer that had previously flown under the radar.

“Not every environmental factor or behavior we study leaves a mark on our genome,” said Alexandrov. “But we’ve found that colibactin is one of those that can. In this case, its genetic imprint appears to be strongly associated with colorectal cancers in young adults.

Ongoing work

The team’s latest discovery raises a host of new questions. How are children being exposed to colibactin-producing bacteria, and what can be done to prevent or mitigate that exposure? Are certain environments, diets or lifestyle behaviors more conducive to colibactin production? How can people find out if they already have these mutations?

The team is investigating several hypotheses while also further examining the correlation between colibactin and the risk of early-onset colorectal cancer. In addition, they are exploring whether the use of probiotics could safely eliminate harmful bacterial strains. They are also developing early detection tests that analyze stool samples for colibactin-related mutations.

In the meantime, the team is continuing its global search for cancer-linked mutational signatures. In the recent Nature study, the team also found that colorectal cancers from specific countries—particularly Argentina, Brazil, Colombia, Russia, and Thailand—showed an increase in certain mutational signatures. This suggests that local environmental exposures may also contribute to cancer risk.

“It’s possible that different countries have different unknown causes,” said Díaz-Gay, who is launching a new phase of the study in his newly established lab at the Spanish National Cancer Research Center (CNIO) in Madrid, Spain. “That could open up the potential for targeted, region-specific prevention strategies.”

Alexandrov noted a broader implication of the research: that many cancers may originate from environmental or microbial exposures in early life, long before diagnosis.

“This reshapes how we think about cancer,” he said. “It might not be just about what happens in adulthood—cancer could potentially be influenced by events in early life, perhaps even the first few years. Sustained investment in this type of research will be critical in the global effort to prevent and treat cancer before it’s too late.”

Reference: “Geographic and age variations in mutational processes in colorectal cancer” by Marcos Díaz-Gay, Wellington dos Santos, Sarah Moody, Mariya Kazachkova, Ammal Abbasi, Christopher D. Steele, Raviteja Vangara, Sergey Senkin, Jingwei Wang, Stephen Fitzgerald, Erik N. Bergstrom, Azhar Khandekar, Burçak Otlu, Behnoush Abedi-Ardekani, Ana Carolina de Carvalho, Thomas Cattiaux, Ricardo Cortez Cardoso Penha, Valérie Gaborieau, Priscilia Chopard, Christine Carreira, Saamin Cheema, Calli Latimer, Jon W. Teague, Anush Mukeriya, David Zaridze, Riley Cox, Monique Albert, Larry Phouthavongsy, Steven Gallinger, Reza Malekzadeh, Ahmadreza Niavarani, Marko Miladinov, Katarina Erić, Sasa Milosavljevic, Suleeporn Sangrajrang, Maria Paula Curado, Samuel Aguiar, Rui Manuel Reis, Monise Tadin Reis, Luis Gustavo Romagnolo, Denise Peixoto Guimarães, Ivana Holcatova, Jaroslav Kalvach, Carlos Alberto Vaccaro, Tamara Alejandra Piñero, Beata Świątkowska, Jolanta Lissowska, Katarzyna Roszkowska-Purska, Antonio Huertas-Salgado, Tatsuhiro Shibata, Satoshi Shiba, Surasak Sangkhathat, Taned Chitapanarux, Gholamreza Roshandel, Patricia Ashton-Prolla, Daniel C. Damin, Francine Hehn de Oliveira, Laura Humphreys, Trevor D. Lawley, Sandra Perdomo, Michael R. Stratton, Paul Brennan and Ludmil B. Alexandrov, 23 April 2025, Nature.
DOI: 10.1038/s41586-025-09025-8

Funding: Cancer Research UK, National Institutes of Health, Wellcome Trust

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