Childhood exposure to a toxin produced by E. coli could be contributing to the rise of bowel cancer in under-50s, according to research funded by Cancer Research UK.
Produced by certain strains of Escherichia coli that reside in the colon and rectum, colibactin is a toxin capable of altering DNA. An international team of researchers, led by the University of California San Diego, has found 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 in Nature, analysed 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 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.”
This work - part of Cancer Grand Challenges team Mutographs and 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.
