Background

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. While the incidence of CRC is increasing rapidly among younger individuals, the underlying causes remain unclear. Previous studies have primarily focused on dietary and genetic factors, which have limitations in fully explaining the characteristics of early-onset CRC patients. Researchers have increasingly focused on the hypothesis that gut microbiota may play a role in the development of cancer. In this context, colibactin, a toxin produced by certain strains of Escherichia coli, has been shown to cause DNA damage and mutations in human cells. However, the frequency of colibactin-induced genetic mutations in actual patients and the stage of tumor development at which these mutations occur have not been fully elucidated. In particular, this study is the first to conduct an integrated analysis linking genomic and fecal metagenomic data in an East Asian population.

Key Findings

A joint research team from the Tokyo University Institute of Medical Science, led by Professor Tatsuhiko Shibata, and the Osaka University Graduate School of Medicine, led by Professor Shinichi Yachida, conducted whole-genome sequencing (WGS) and transcriptome sequencing (RNA-seq) on tumor and normal tissues from 200 Japanese CRC patients. They also combined this with metagenomic sequencing data obtained from the patients' fecal samples to comprehensively elucidate the relationship between host genetics and the gut microbiome. The analysis revealed that 44.8% of the entire CRC patient population exhibited SBS88 and ID18, which are unique mutational signatures associated with colibactin. This is more than double the global average frequency of approximately 19%. In particular, age-related analysis showed that the proportion was significantly higher in younger patients. In the early-onset CRC patient group (under 40 years of age), the proportion of patients with colibactin-associated mutations was as high as 70%. Patients under 50 years of age were found to be 3.3 times more likely to have these mutations compared to patients over 70 years of age. Mathematical modeling analysis, which tracks the timing of gene mutations, further demonstrates the underlying mechanism. In the case of APC gene mutations, which occur in the early stages of colorectal cancer development, colibactin-induced damage is estimated to have occurred in patients under the age of 10 during childhood. This suggests that genetic scars caused by gut microbial toxins in childhood accumulate over decades and eventually develop into tumors. These mutations were also observed in other major driver genes, including BRAF and TP53.

Significance and Future Directions

This study provides molecular-level evidence that specific toxins from gut microbiota can induce mutations in tumor suppressor genes and promote CRC development. By identifying colibactin as a strong causative agent of early-onset CRC, this research is expected to pave the way for a paradigm shift in cancer prevention strategies for younger individuals. However, colibactin-producing bacteria are often not detected in stool samples at the time of cancer diagnosis. This suggests that it is difficult to expect therapeutic effects by simply eliminating colibacteria after cancer diagnosis, and that preventive measures should be taken proactively during childhood or adolescence. Future studies should focus on identifying populations at risk based on large-scale cohort studies, and on precisely determining the timing of exposure to colibactin-producing bacteria and genetic susceptibility.