Geographic and age variations in mutational processes in colorectal cancer

A new study led by the International Agency for Research on Cancer (IARC) suggests that exposure to specific bacteria during childhood may trigger genetic changes that could increase the risk of developing colorectal cancer decades later and contribute to the alarming increase in colorectal cancer rates among young adults worldwide.

Based on the analysis of genomes of 981 patients with colorectal cancer from 11 countries across four continents, the findings revealed significant geographical and age-related differences in the DNA mutations that lead to early-onset colorectal cancer.

The study, which was published in Nature, is part of the Cancer Grand Challenges Mutographs project and is funded by Cancer Research UK. It was conducted in collaboration with the University of California San Diego and the Wellcome Sanger Institute.

The researchers found a distinctive mutational signature linked to colibactin, a cancer-causing substance produced by certain gut bacteria, which was especially common in individuals diagnosed with colorectal cancer before the age of 50 years. This mutational footprint appeared to occur early in life and was associated with early mutations in the APC gene, a key driver in the development of colorectal cancer.

Over the past two decades, rates of colorectal cancer in people younger than 50 years have doubled in many countries. Whereas lifestyle and environmental factors have been suspected, this study provides molecular evidence that mutagenic exposures in childhood (potentially through the microbiome) could be accelerating the onset of the disease.

The study also identified unique, unexplained mutational patterns in patients from Argentina, Brazil, Colombia, the Russian Federation, and Thailand, highlighting the role of regional exposures and the need for country-specific prevention strategies.

Díaz-Gay M, dos Santos W, Moody S, Kazachkova M, Abbasi A, Steele CD, et al.
Geographic and age variations in mutational processes in colorectal cancer
Nature. Published online 23 April 2025;
https://doi.org/10.1038/s41586-025-09025-8

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