Environmental Factors and Epigenetic Drivers of Early-Onset Colorectal Cancer

Researchers have identified an exposome footprint—a specific set of environmental and lifestyle exposures—linked to colorectal cancer in patients younger than 50 years of age. The findings, published April 30, 2026, in Nature Medicine, suggest that the rising incidence of early-onset colorectal cancer is likely driven by environmental factors rather than purely genomic mutations.

The study utilized epigenetic signatures to uncover these drivers. Epigenetics involves a system that activates or deactivates genes without altering the underlying DNA sequence. One primary mechanism is DNA methylation, where small chemical marks attach to DNA, acting as markers that dictate which parts of the genetic code are read or skipped.

The Role of the Exposome

The exposome refers to the totality of exposures an individual encounters throughout their life, including diet, stress, and toxins. By comparing DNA methylation patterns in patients under 50 with those over 50, the research team confirmed the influence of several modifiable risk factors, including smoking, diet, and education level.

If we imagine the genome as a book, epigenetic marks don’t change the text, but function like post-its or markers that indicate which chapters should be read and which should be skipped. These post-its can be added or removed depending on the environment and lifestyle—diet, stress, or exposure to toxins—influencing how the same book is interpreted over time.

José A. Seoane, PhD, Head of VHIO’s Cancer Computational Biology Group

The study, co-authored by researchers from the Vall Hebron Institute of Oncology (VHIO), specifically explored how these epigenetic marks could distinguish early-onset cases from late-onset cases. This approach addresses a critical gap in previous research, as many earlier studies compared early-onset patients only to age-matched controls, often finding the same risk factors as those associated with older patients.

Clinical Significance of Early-Onset Colorectal Cancer

Colorectal cancer is currently the third most common cancer worldwide and the second-leading cause of cancer-related deaths globally. While approximately 90% of worldwide cases and deaths occur in people over 50, there has been a disproportionate increase in incidence among younger populations.

In the United States, this trend has reached a critical point. Early-onset colorectal cancer is now the leading cause of cancer-related death in men under 50 and the second-leading cause in women under 50.

Medical professionals have noted that while these younger patients exhibit distinct clinical and pathologic characteristics, their genomic molecular alterations remain similar to those in older patients. This similarity suggests that the drivers of the disease in younger people are not found in the DNA sequence itself, but in how those genes are expressed due to external influences.

Uncertainties and Future Directions

Despite the identification of these epigenetic fingerprints, researchers emphasize that many questions remain. The complexity of the exposome makes it difficult to isolate a single cause, as environmental exposures across a lifespan are rarely measured with perfect accuracy.

The identification of these signatures provides a new framework for understanding why colorectal cancer is appearing more frequently in younger adults. By focusing on the exposome footprint, scientists hope to better identify modifiable risk factors that could lead to more effective prevention and screening strategies for those under 50.