Colibactin, a mutagen produced by bacteria, is a likely contributor to the increasing incidence of early-onset colorectal cancer, according to the results of a genetic analysis of cancers from patients in intermediate- and high-incidence countries around the world.
The study “provides the strongest evidence to date that colibactin … causes specific DNA mutations that can initiate colorectal cancer,” according to senior author Ludmil Alexandrov, PhD, a professor in the Departments of Cellular and Molecular Medicine and Bioengineering at the University of California, San Diego. The investigators “identified a clear mutational signature linked to colibactin and showed that it is present in a substantial proportion of CRC tumors, particularly early-onset cases.”
Characterization of the drivers of early-onset CRC is a gap in the current literature, according to Samir Gupta, MD, a professor in the Division of Gastroenterology and the co-lead of the Cancer Control Program at UC San Diego Moores Cancer Center. He noted that “there has been a dramatic relative increase in incidence of young-onset CRC, with each generation born since 1960 experiencing higher risk for early-onset CRC than the prior. Further, it looks now that increased risk is being carried forward to middle age.” Dr. Gupta cited changes in obesity, alcohol exposure and diet as potential contributing factors, but said “environmental exposures have been largely unexplored.”
Study Details
Dr. Alexandrov and his co-investigators performed whole-genome sequencing on CRC samples from adults with no prior treatment for CRC from 11 countries in Asia, Europe, North America and South America (Nature 2025;643[8070]: 230-240).
Among 981 cases of CRC, 45.7% occurred in women and 132 were early-onset cancer. Cancers were evenly distributed across the proximal colon (320 cases), distal colon (333 cases) and rectum (326 cases), with two cases in unspecified sites. The early-onset cases were more common in the distal colon and rectum relative to the proximal colon.
After sequencing, the cancers were divided into microsatellite stability (MSS) and microsatellite instability samples, which were DNA mismatch repair-proficient and -deficient, respectively. The investigators focused their main analyses on the MSS samples (81.8%, 802 total, 97 early-onset cancer).
Among these MSS samples, single base substitutions (SBS) and small insertions and deletions (ID) were less common among early-onset cases than they were in cases in patients aged 50 years and older (SBS fold-change, 0.92; P=0.045; ID fold-change, 0.90; P=0.018), although the average SBS and ID mutation spectra of early- and late-onset cases were similar. There were no statistically significant differences in the burden of average mutational spectra of doublet base substitutions, copy number alterations or structural variants in early- and late-onset cases.
The mutational profiles of the cancers across the 11 countries were generally similar, but the investigators identified certain mutational signatures that were more prevalent in individual countries. They further explored how these different mutational signatures were related to age-standardized CRC incidence rates (ASR) to better understand of the implications of different mutational processes. Of note, colibactin-induced mutational signatures (SBS88 and ID18), among others, were associated with increased ASR overall as well as early-onset cancer.
Defined as the presence of either SBS88 or ID18, colibactin exposure was found in 21.1% of the 802 MSS samples. SBS88 and ID18 were, respectively, 2.5 (Q=0.006) and 4 (Q=3.7’10-7) times as common in early-onset cases than in cases diagnosed in patients 50 years of age and older. These colibactin-induced signatures became less common as age of diagnosis increased. The median age of diagnosis specifically in the distal colon and rectum was lower in the colibactin-exposed patients than in the unexposed group (distal: 57 vs. 66 years; Q=5.2’10-7; rectum: 63 vs. 66 years; Q=0.025).
The investigators also assessed the clonal structure of the samples to characterize mutations as early clonal, late clonal or subclonal during CRC development. The colibactin-induced signatures were found to be enriched in early rather than late clonal mutations, which the investigators noted was “consistent with the presence of these mutational signatures in normal colorectal epithelium.” This early clonal enrichment was found in both early- and late-onset cancer cases.
When assessing the contribution of SBS88 and ID18 to driver gene mutations, the investigators found that, among colibactin-exposed cases, 8.3% of all SBS and ID driver mutations and 15.5% of APC driver mutations could be accounted for by colibactin-induced mutations. The researchers found no difference between early- and late-onset cases.
Bacteria that carry the pks pathogenicity island produce colibactin. Thus, the investigators assessed whether patients with colibactin-induced mutations had pks+ bacteria. They found no association between the mutations and bacteria presence, which they said could be due to “imprinting of SBS88 and ID18 on the colorectal epithelium during an early period of life when pks+ bacteria were present, followed by the natural plasticity of the microbiome over subsequent decades, leading to the loss of pks+ bacteria.”
Key Takeaways
Dr. Alexandrov noted the importance of further research to better understand the role of colibactin exposure in CRC carcinogenesis, including characterizing “the timing, duration and frequency of exposure” to colibactin-producing bacteria and understanding how “the interplay between host genetics, immune response, microbiome composition and environmental factors” informs susceptibility to colibactin-induced mutations and carcinogenesis.
Dr. Gupta also stressed the importance of additional research to “explore what might be driving the increased exposure to colibactin-generating bacteria,” as well as “what may be driving some of the mutational patterns that were overrepresented in early-onset CRC, for which the upstream drivers remain completely unexplained.”
Dr. Alexandrov said his team’s work “suggests that bacterial exposures in the gut, particularly during childhood or early life, may play a previously underappreciated role in driving colorectal tumorigenesis.” These findings “highlight the potential for future” screenings and interventions, he added, including “stool-based screening tools that detect colibactin-induced DNA damage long before cancer develops” and “the possibility that modulating the microbiome in childhood—through antibiotics, probiotics or dietary interventions—might eventually reduce CRC risk in high-risk individuals.”
—Natasha Albaneze, MPH
Dr. Alexandrov reported financial relationships with Acurion and Inocras. He holds European Patent Application No. EP25305077.7, which focuses on using the colibactin mutational signature in stool samples for the detection of early-onset colorectal cancer. Dr. Gupta reported no relevant financial disclosures.
This article is from the September 2025 print issue.