An international team led by UC San Diego has uncovered that early life exposure to colibactin, a DNA damaging toxin produced by certain E. coli strains, leaves a distinctive mutational signature that is 3.3 times more prevalent in colorectal cancers diagnosed before age 40 compared to those after age 70. This finding, based on the analysis of 981 tumor genomes from 11 countries, suggests that colibactin exposure in childhood may seed mutations decades before early onset colorectal cancer emerges.
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.”
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