Apr 30th 2025|6 min read
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AT EMERGENCY DEPARTMENTS across the world, patients are presenting with undiagnosed cancers at an advanced stage. Their tumours have gone unnoticed for so long because these individuals defy the picture of the typical cancer patient: they are young, seemingly healthy, and without any family history of the disease. Worryingly, their numbers are rising. Increased incidence of early-onset cancer, as the diagnosis is called for adults under 50, has been documented for more than a dozen cancers, including those of the breast, bowel, lung, ovaries and pancreas.
The numbers for bowel cancer, the third-most-common type worldwide, are rising particularly fast (see chart). Compared with Americans born around 1950, projections suggest that those born around 1990 are twice as likely to develop colon cancer by the time they turn 50, and four times as likely to develop rectal cancer. The trend appears to be worsening, with each generation having a greater risk than its predecessors. Similar patterns have been reported in at least 27 other countries. The causes have been hard to ascertain. Observational studies linking bowel cancer to a variety of non-hereditary factors including obesity, alcohol intake and low physical activity have not uncovered anything unique to early-onset cases.
Chart: The Economist
New genomic methods could change that. These allow scientists to identify what are known as mutational signatures, distinctive changes induced in a cell’s genome by specific external influences. Tobacco has some, for example; so does ultraviolet radiation. If the same mutation, brought about in the same way, occurs in enough people with early-onset cancer, a case can be made that a culprit has been found. A paper published in Nature on April 23rd suggests just such a breakthrough: namely, that exposure to a common gut bacterium in early childhood may contribute to premature bowel cancer.
To reach their conclusion, the researchers—an international collaboration led by scientists at the University of California, San Diego—analysed the genomes of 981 colorectal-cancer tumours from 11 countries. One of the most common mutational signatures that they found, especially in younger patients, was that of colibactin, a toxin released by a number of bacteria, including a widespread strain of Escherichia coli. It was present in more than 50% of the tumours from patients younger than 40, but less than 20% of those above 60.
Sequencing the mutations revealed yet another surprise; namely, that the damage from colibactin occurred in the very early stages of tumour development, as well as in the specific gene whose impairment triggers bowel cancer. The scientists also found that these mutations typically arose in the first ten years after birth.
When the researchers went on to analyse stool samples that had been collected from children in about 20 countries for a prior study, they discovered that those from countries with higher rates of early-onset cancer were more likely to carry the colibactin strain of E. coli. Why this should be the case remains unclear, though some researchers suspect that rising rates of antibiotics use and caesarean births may sufficiently disrupt children’s microbiomes to allow for this strain of E. coli to take root. Others worry about probiotics that contain this bacterium, some of which are currently used to treat diarrhoea.
The transformation of a single carcinogenic mutation into full-blown cancer normally takes years or decades. It typically starts in middle age when mutations of all sorts start to pile up. But early colibactin mutations follow a different script. “If you get the first hit of a cancer-driver at age five, you essentially become 20-30 years ahead of schedule for getting colorectal cancer,” says Ludmil Alexandrov from the University of California San Diego, one of the study’s authors. Alberto Bardelli of the University of Turin, who was not involved in the study, says the effect on a person’s cancer risk is akin to a hereditary genetic predisposition for the disease.
It may be too early to lay all the blame at colibactin’s door. The researchers found two other mutational signatures which affected cancer-related genes and were also more widespread in younger patients. Whereas 50% of these had the signature of colibactin, 70% to 80% had some combination of the three. Dr Alexandrov and his colleagues now hope to identify the causes of these two new signatures, though further research will be needed to tease out their individual contributions.
There are other twists to disentangle. About a third of healthy adults carry colibactin-producing E. coli, of whom only a small fraction go on to develop colorectal cancer. An animal study published in March in Nature Microbiology revealed that these bacteria thrived in mice fed a diet low in carbohydrates and soluble fibre; the mice also had more colibactin damage to the DNA of colon cells than mice fed other diets. The lack of fibre, which feeds various beneficial gut bacteria, appeared to weaken the protective mucous barrier of the colon. When these bacteria are starved, they are overtaken by pathogenic bacteria that destroy that protective layer, exposing the colon’s cells to colibactin.
A different type of study, conducted by a group led by Shuji Ogino at Harvard and published in 2022, pointed in the same direction: in a cohort of health professionals followed over time, closer adherence to a Western-style diet (high on red and processed meat, sugar and refined grains and low on fibre) was associated with colorectal tumours that contained greater amounts of colibactin-producing E. coli. Other factors may also be at play. A number of research groups are investigating the role of microplastics, exposure to which has grown in recent decades, in weakening the colon’s protective barrier.
The identification of a mechanism for early-onset cancer also opens the possibility of treatment. Three main pathways are being explored: namely, drugs that inhibit _E. coli’_s effects; probiotics that help beneficial bacteria in the gut outcompete it; and bespoke bacteria-infecting viruses known as phages. Such research, though promising, has so far been done only in cell cultures or lab animals; potential treatments will not be available anytime soon.
Understanding the risks and benefits of treatment, especially in children, will also take time. To this end, Dr Alexandrov’s team is now analysing stool samples from children in about 20 countries to find out how often the bacteria induce the worrying mutations in those who carry it. They also hope to develop tests capable of spotting colibactin-induced mutations in stools within the next five years. In theory, doctors could then identify individuals who would benefit from closer monitoring and early intervention with existing techniques. The tests cannot come too soon. ■
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This article appeared in the Science & technology section of the print edition under the headline “The root of the problem”
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