Researchers may have identified the bacterial toxin colibactin as a potential factor contributing to the concerning rise in early-onset colorectal cancer, according to a novel study published by Díaz-Gay et al in Nature. The findings demonstrated a substantial enrichment of colibactin-related mutations specifically in early-onset colorectal cancer cases.
Background
Once considered a disease among older adults, colorectal cancer is now on the rise among young patients in at least 27 countries. Its incidence in adults younger than age 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 mortality among young adults by 2030.
Prior to this recent study, the mechanisms behind the surge in early-onset colorectal cancer cases 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, fueling speculation about potential hidden environmental or microbial exposures.
DNA mutations caused by environmental exposures such as ultraviolet radiation and bacterial toxins as well as lifestyle behaviors like smoking and drinking alcohol could provide a unique mutational signature in the genome that may help to pinpoint the pathogenesis of certain cancer types.
Produced by certain strains of Escherichia coli that reside in the colon and rectum, colibactin is a toxin capable of altering DNA. Although previous studies have identified colibactin-related mutations in roughly 10% to 15% of all colorectal cancer cases, those studies either focused on late-onset cases or did not distinguish between early- and late-onset disease.
“When we started this project, we weren’t planning to focus on early-onset colorectal cancer,” explained co–lead study author Marcos Díaz-Gay, PhD, of the Spanish National Cancer Research Center in Madrid. “Our original goal was to examine global patterns of colorectal cancer to understand why some countries have much higher rates than others, [b]ut 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,” he added.
Study Methods and Results
In this study, the researchers analyzed 981 colorectal cancer genomes from patients with early- and late-onset disease across 11 countries with varying colorectal cancer risk levels.
The researchers reported that exposure to colibactin in early childhood could imprint a distinct genetic signature on the DNA of colon cells, leaving behind specific patterns of DNA mutations that were 3.3 times more common among patients with early-onset colorectal cancer—specifically in adults younger than age 40—compared with among those diagnosed after age 70. The mutational patterns were also particularly prevalent in countries with a 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,” detailed senior study author Ludmil Alexandrov, PhD, Professor in the Shu Chien-Gene Lay Department of Bioengineering and the Department of Cellular and Molecular Medicine at the University of California (UC), San Diego, Deputy Director of the Sanford Stem Cell Fitness and Space Medicine Center, and a member of UC San Diego Moores Cancer Center.
By molecularly timing each mutational signature identified in the study, the researchers demonstrated that colibactin-associated mutations arose early in tumor development, consistent with prior studies showing that such mutations occurred within the first 10 years of life. They also revealed that colibactin-related mutations may account for approximately 15% of APC driver mutations—some of the earliest genetic alterations that directly promote cancer development—in colorectal cancer. As a result, the researchers argued that colibactin-producing bacteria may be silently colonizing the colons of children, initiating molecular changes in their DNA, and potentially paving the way for colorectal cancer to develop long before the presentation of any symptoms.
“If [individuals] acquire one of these driver mutations by the time they’re 10 years old, they could be decades ahead of schedule for developing colorectal cancer, getting it at age 40 instead of 60,” stressed Dr. Alexandrov.
Additionally, colorectal cancers from specific countries—particularly Argentina, Brazil, Colombia, Russia, and Thailand—showed an increase in certain mutational signatures, suggesting that local environmental exposures may contribute to cancer risk. “It’s possible that different countries have different unknown causes,” underlined Dr. Díaz-Gay. “That could open up the potential for targeted, region-specific prevention strategies,” he continued.
Conclusions
Similar strategies have thus far elucidated the mutational processes underlying esophageal cancer, renal cell carcinoma, and head and neck cancers worldwide. This most recent result on colorectal cancer could further expand the global understanding of cancer etiology through mutational signature analysis. By systematically cataloging these mutational patterns across thousands of cancer genomes, the researchers have worked to identify previously unrecognized causes of cancer.
“Not every environmental factor or behavior we study leaves a mark on our genome, [b]ut 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,” stated Dr. Alexandrov.
Although the novel findings provided strong support for this hypothesis, further research may be necessary to establish causality. The researchers plan to resolve questions regarding how children are exposed to colibactin-producing bacteria; which environments, diets, and behaviors are more conducive to colibactin production; how to test for these DNA mutations; and how to mitigate exposure to the bacterial toxin in future studies. They hope to further examine the correlation between colibactin and the risk of early-onset colorectal cancer, explore whether the use of probiotics could safely eliminate harmful bacterial strains, and develop early detection tests to analyze stool samples for colibactin-related mutations. In the meantime, the researchers are continuing their global search for cancer-linked mutational signatures.
“This reshapes how we think about cancer,” Dr. Alexandrov underscored. “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,” he concluded.
Disclosure: The research in this study was supported in part by Cancer Grand Challenges, funded by Cancer Research UK. For full disclosures of the study authors, visit nature.com.
