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News — In an effort to explain a modern medical mystery, an international team of researchers led by the University of California San Diego has identified a potential microbial culprit behind the alarming rise in early-onset colorectal cancer: a bacterial toxin called colibactin.

Produced by certain strains of Escherichia coli that reside in the colon and rectum, colibactin is a toxin capable of altering DNA. Now, scientists report that exposure to colibactin in early childhood imprints a distinct genetic signature on the DNA of colon cells—one that may increase the risk of developing colorectal cancer before the age of 50.

The new study, published on April 23 in Nature, analyzed 981 colorectal cancer genomes from patients with both early- and late-onset disease across 11 countries with varying colorectal cancer risk levels. The findings show that colibactin leaves behind specific patterns of DNA mutations that were 3.3 times more common in early-onset cases (specifically in adults under 40) than in those diagnosed after the age of 70. These mutation patterns were also particularly prevalent in countries with high incidence of early-onset cases.

“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 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 , 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 and bacterial toxins—and lifestyle behaviors like 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 funding, team Mutographs has elucidated the mutational processes underlying , , and 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.”

Full study: “.”

This work is supported in part by Cancer Research UK, the U.S. National Institutes of Health, David and Lucile Packard Foundation, UC San Diego Sanford Stem Cell Institute and the Wellcome Trust.

Disclosures: Ludmil B. Alexandrov is a co-founder, CSO, scientific advisory member and consultant for io9. Alexandrov has equity in and receives income from io9. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. Alexandrov’s spouse is an employee of Hologic, Inc. Study co-author Erik N. Bergstrom is a consultant for io9, has equity and receives income. Alexandrov and study co-author Ammal Abbasi declare U.S. provisional patent application filed with UC San Diego with serial number 63/366,392. Alexandrov and Bergstrom declare U.S. provisional patent application filed with UC San Diego with serial number 63/269,033. Alexandrov also declares U.S. provisional applications filed with UC San Diego with serial numbers: 63/289,601; 63/412,835; as well as an international patent application PCT/US2023/010679. Alexandrov is also an inventor of a U.S. Patent 10,776,718 for source identification by non-negative matrix factorization. Study co-author Michael R. Stratton is founder, consultant and stockholder for Quotient Therapeutics. Ludmil B. Alexandrov, Marcos Díaz-Gay and study co-authors Paul Brennan, Sandra Perdomo, Michael R. Stratton and Sarah Moody declare a European patent application with application number EP25305077.7. Study co-author Trevor D. Lawley is a co-founder and CSO of Microbiotica. All other authors declare that they have no competing interests.