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The numbers don’t lie: Colorectal cancer (CRC) has been on the rise in younger people in the United States for over two decades.

While the data show a clear trend, researchers still face a glaring unanswered question: Why is this happening?

A recent report in Nature may offer an important clue to start unraveling this early-onset CRC mystery.

What the Study Found

The new analysis found that childhood exposure to a carcinogenic toxin known to cause DNA damage is strongly linked to the development of early-onset CRC.

The bacterial toxin, called colibactin, is produced by certain strains of Escherichia coli and other bacteria — more specifically, polyketide synthase (PKS)–positive strains. Previous research has found colibactin-related mutations can occur in up to 15% of CRC cases overall, but a link to early-onset disease has been less clear.

In this recent genetic analysis, investigators led by Marcos Díaz-Gay, PhD, analyzed CRC biopsies from 981 patients across 11 countries and 4 continents. The team tracked DNA damage from colibactin by identifying distinctive mutational signatures — called SBS88 and ID18 — left by the toxin.

Díaz-Gay and colleagues found that these mutational signatures were 3.3 times more common in patients diagnosed before 40 years of age than in those over 70 years.

Colibactin exposure was also linked to about a quarter of mutations that inactivate the colorectal tumor suppressor gene APC.

However, epidemiologic factors linked to CRC, such as body mass index, diet, and lifestyle, were not considered in the study, which the investigators noted is a key limitation.

“Our results show for the first time an association between the presence of colibactin-induced mutational signatures and early-onset colorectal cancer,” Díaz-Gay, a genomic researcher at the Spanish National Cancer Research Center, Madrid, Spain, and colleagues wrote.

“Prior studies have indicated that mutagenesis due to colibactin exposure can occur within the first decade of life and then ceases,” the investigators explained. But “this ‘head start’ could plausibly result in an increased risk of early-onset cancers.”

What the Study Means

Trevor Graham, PhD, a professor of genomics and evolution at The Institute of Cancer Research, London, England, helped put the study findings into context.

Others have proposed that colibactin “could have a role in causing early-onset disease,” Graham commented in a statement from the UK nonprofit Science Media Centre. “This work provides [the] strong[est] data yet that the hypothesis is correct.”

Plus, Graham added, “This is very good quality research. The authors have collected bowel cancers from countries around the world and performed whole genome sequencing on them.”

“Most importantly,” he said, the colibactin mutations were more common in people who got bowel cancer before 50 years of age, which “suggests the mutations caused by these bugs in the bowel could be a cause of early-onset bowel cancer, although further studies are needed to confirm this.”

Although the study doesn’t prove causation, “this is a very important finding,” Alan Venook, MD, a gastrointestinal medical oncologist and CRC specialist at the University of California, San Francisco, told Medscape Medical News. “This gives us a hook to understand what’s going on.”

However, “it’s not at all likely that this single entity is entirely responsible for early-onset CRC,” Venook clarified.

But if childhood exposure to colibactin is responsible, at least in part, for the growing incidence of early-onset CRC, it would suggest that PKS-positive bacteria have become more common in the gut microbiome of younger people over the past few decades. PKS-positive E coli are common, in general — found in up to 20% of healthy people and about 67% of patients with CRC.

If these bacteria are becoming more common in younger people, the reason isn’t yet clear. “The working hypothesis is overuse of antibiotics in young kids,” said Venook, who is collaborating with colleagues to launch an additional multi-institution investigation into the issue.

There are also clinical implications if the findings pan out, Venook said.

This work could lead to a diagnostic test — perhaps one looking for circulating mutational DNA in the blood — that could “give us a leg up on who’s at risk for early-onset CRC,” Venook said. “That’s how this could really make a difference.”

The work was funded by the National Institutes of Health, Cancer Research UK, and others. Several investigators disclosed ties to io9, Inocras, Hologic, Quotient Therapeutics, and Microbiotica. Venook didn’t have any disclosures; disclosure information for Graham was unavailable.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.