A global genomic study of colorectal cancer (CRC) has revealed that certain age-related and regional patterns in tumor mutations may be linked to early-life exposure to specific bacteria. The study, which analyzed nearly 1,000 whole-genome sequences of colorectal tumors from patients in 11 countries, provides new insights into why early-onset colorectal cancer is increasing, particularly among individuals under the age of 50.
The research focused on microsatellite-stable colorectal cancers, which comprise the majority of CRC cases and are not typically associated with inherited syndromes like Lynch syndrome. While overall mutation rates were similar between early- and late-onset cancers, specific patterns of DNA damage were found to be more common in younger patients. In particular, the signatures known as SBS88 and ID18, caused by a toxin called colibactin produced by certain strains of Escherichia coli, were enriched in early-onset cases and in countries with high CRC incidence rates.
Colibactin exposure appears to leave a lasting genetic imprint early in life, with the associated mutations found in the earliest stages of tumor development. This suggests that the mutagenic event may occur decades before cancer is diagnosed. In fact, tumors with SBS88 and ID18 mutations often showed alterations in the APC gene, a critical driver in CRC development. About one-quarter of APC gene alterations in affected tumors were linked to colibactin-induced damage.
The study’s international design revealed that these colibactin-related mutations were significantly more prevalent in some regions, indicating possible geographic differences in bacterial exposure. However, the presence of the mutational signatures did not always correspond with current bacterial colonization, implying that the initial exposure and resulting genetic changes may have occurred long before the samples were collected.
"This reshapes how we think about cancer," said senior author, Ludmil Alexandrov. "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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