Could Kids' Gut Bacteria Trigger Young Colorectal Cancer?

Medscape

2 days ago

According to a study published in Nature by an international team led by the University of California, San Diego, childhood exposure to the bacterial toxin colibactin could drive early-onset colorectal cancer (CRC).
The first author is Marcos Díaz-Gay, PhD, head of the new Digital Genomics Group at the Spanish National Cancer Research Center (CNIO) in Madrid, Spain.
CRC is considered a disease associated with aging; however, its incidence in adults younger than 50 years has approximately doubled each decade over the past 20 years in various countries. If current trends persist, it could become the leading cause of cancer-related deaths among young adults by 2030.
Childhood Exposure
Díaz-Gay told the Medscape Spanish edition that it remains unclear what factors over the past two decades have driven the rise in CRC among younger adults. 'Our study is one of the first to address this question, and it offers a partial answer. It supports the hypothesis that colibactin exposure contributes to this increase; however, the finding is correlative rather than causal. We need further evidence to prove causality,' said Díaz-Gay.
He noted that although diet and lifestyle have changed over the past 20 years, 'but the changes occurred earlier, since these people are currently between 20 and 50 years old. With respect to colibactin, we are talking about exposures in the first 10 years of life,' he added.
He emphasised that the study does not claim that colibactin is the cause of all cases in young patients, nor does it exclude its role in older adults.
'It is true that we see it more frequently in people under 50, but we also observe it in older people; in fact, 10% of those over 50 also have these mutations,' said Díaz-Gay.
Mutational Patterns
Colibactin is a toxin produced by certain Escherichia coli strains that damages the cellular DNA. The study showed that exposure to this toxin during early childhood imprints a characteristic genetic signature on the DNA of colon epithelial cells.
'The mutational pattern that colibactin imprints on the genome was already known,' Díaz-Gay explained.
In 2020, Hans Clevers and Spanish collaborators conducted a study using organoids, in which a specific mutational profile induced by the toxin was observed.
Michael R. Stratton's group subsequently identified the same profile in normal colon cells, noting its emergence and enrichment during childhood, when tumours are at their earliest developmental stages and are clearly enriched at that time. 'We confirmed that they are also present in early tumour stages,' said Díaz-Gay.
The novel finding of this study was that the mutational patterns associated with colibactin were more frequent in patients younger than 50 years. 'We identified this internationally in nearly 1000 sequenced patients,' he said.
Mutation Burden
The investigators analysed 981 CRC genomes from 11 countries. The results showed that colibactin leaves specific DNA mutation patterns, which are true mutational signatures. These signatures are 3.3 times more frequent in adults diagnosed before the age of 40 years than in those diagnosed after the age of 70 years.
Moreover, the overall colibactin signatures are especially prevalent in countries with high rates of early-onset CRC.
The study found no significant differences in cancers with microsatellite instability but observed variations in the mutation burden and signatures in 802 microsatellite-stable cases. Multiple signatures, most of which have unknown aetiology, showed variable prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure.
The SBS88 and ID18 signatures, caused by the mutagen colibactin, showed higher mutation loads in countries with higher CRC incidence. SBS88 and ID18 were also enriched in early-onset CRC, being 3.3 times more common in those diagnosed before the age of 40 years and appearing in the earliest stages of tumour development. Colibactin exposure is linked to driver mutations in the tumour suppressor gene APC ; the mutational signature ID18 accounts for approximately 25% of APC insertions or deletions in colibactin-positive tumours.
Conceptual Shift
'These mutation patterns are a kind of historical record in the genome,' said Ludmil Alexandrov, PhD, professor in the Shu Chien-Gene Lay Department of Bioengineering and the Department of Cellular and Molecular Medicine at University of California, San Diego, who is also a member of University of California, San Diego Moores Cancer Center and deputy director of Sanford Stem Cell Fitness and Space Medicine Center, San Diego, and lead author of the study, in a CNIO press release.
'If someone acquires one of these driver mutations at age 10,' Alexandrov explained, 'they could be decades ahead of the curve in developing colorectal cancer and develop it at age 40 instead of 60.'
Alexandrov also pointed out the conceptual shift these results represent; many cancers can be traced to environmental or microbial exposures in the first years of life, long before diagnosis. 'This changes the way we think about cancer. It is not just about what happens in adulthood but also in the first decade of life, even in the first few years.'
'Until now, we had no satisfactory explanation for the increased incidence of CRC in young patients.' Various hypotheses have been proposed, but without conclusive data. 'The newly published study offers a solid and interesting hypothesis to explain this phenomenon and suggests a potential preventive strategy,' Andrés Muñoz, MD, a medical oncologist at Gregorio Marañón University Hospital in Madrid, Spain, told Medscape Spanish edition.
On whether it would be appropriate to implement screening protocols to detect these cases in young people, Muñoz said: 'Before any screening or therapeutic protocol is introduced, these highly relevant findings must be validated and replicated in other studies and patient cohorts.'
He added that genetic analyses to detect these mutations are currently only available at the research level, making their clinical application difficult. Díaz-Gay explained: 'We perform whole genome sequencing of tumour biopsies and blood cells as normal tissue to identify tumour mutations, but this is not applicable in clinical practice, where specific genes relevant to a given tumour are analysed.'
He noted a desire to detect these mutations non-invasively via liquid biopsy or stool analysis rather than genetic testing but said that the effort is at an early stage.
Geographic Variation
The study found that SBS88 and ID18 were prevalent in cancers from specific countries — namely Argentina, Brazil, Colombia, Russia, and Thailand — suggesting that local environmental exposure may contribute to cancer, although the factors remain unknown.
Spain was not included in this part of the study design, which focused on molecular differences among those countries, 'but ultimately the primary objective became recognising differences between age groups,' Díaz-Gay said.
Although country-specific differences were found, the overall similarities in these tumours were considerable: 'There are specific genetic signatures, though not for colibactin, but in the mutational processes driving tumours. We have seen very concrete signatures in Argentina and Colombia; in these cases, though we could not determine the source, they could be related to microbial environmental exposures or other toxins.'
On other little-known environmental carcinogens, Díaz-Gay said that none stand out for the colon at present but that mutation pattern analysis has yielded major discoveries in recent years: 'New environmental factors causing kidney cancer mutations have been identified — for example, aristolochic acid, a highly mutagenic carcinogen linked to traditional medicine plants in countries such as Taiwan,' he explained.
He added that some high-risk cancer compounds are not associated with mutations, 'which is notable and the subject of much current research.'
Future Research
The authors outlined the key questions they would like to address in later phases of this research: How are children exposed to colibactin-producing bacteria, and how can that exposure be prevented? Do specific diets and lifestyles promote colibactin production? How can carriers of these mutations be identified? Trials are underway to assess whether probiotics can eliminate harmful strains and develop stool-based tests for the early detection of colibactin-associated mutations.
Díaz-Gay has filed a European patent application with application number EP25305077.7. Conflicts of interest for the other authors are detailed in the original publication. Muñoz has declared having no relevant financial conflicts of interest.