Epigenetic fingerprints may help explain how environmental exposures contribute to colorectal cancer in people under 50.
Why is colorectal cancer becoming more common in people under 50 when their tumors often lack obvious genetic differences from those diagnosed later in life? A new study suggests part of the answer may be written not in the DNA sequence itself, but in chemical marks left behind by a lifetime of environmental and lifestyle exposures.
A study led by José A. Seoane, head of the Vall d’Hebron Institute of Oncology’s (VHIO) Computational Biology Group, has identified for the first time the exposome footprint, the collection of environmental and lifestyle exposures, in colorectal cancer among patients younger than 50 by using epigenetic signatures. Published on 21 April 2026 in Nature Medicine, the research compared DNA methylation patterns in patients under and over 50 and confirmed the influence of factors including diet, education level, and smoking.
Colorectal cancer (CRC) is the world’s third most common cancer and the second leading cause of cancer-related death. Its incidence and mortality generally rise with age. Although an estimated 90% of cases and deaths worldwide occur in people older than 50, early onset CRC (EOCRC), generally defined as CRC diagnosed in people younger than 50 years of age, has been increasing disproportionately in recent years. In the United States, early onset colorectal cancer (EOCRC) is already the leading cause of cancer-related death in men under 50 and the second leading cause in women under 50.
“Colorectal cancer in patients under fifty years of age presents particular clinical and pathological characteristics. However, at the genomic level, the molecular alterations are similar, and no specific alterations have been identified,” explained Elena Élez, head of the Digestive Tumors Unit at the Vall d’Hebron University Hospital and VHIO’s Gastrointestinal Tract Tumors Group. “Therefore, the causes for rising early-onset colorectal cancer remain unclear,” said Iosune Baraibar, a Clinical Investigator of VHIO’s Gastrointestinal Tract Tumors Group.
The exposome influence in EOCRC
A growing line of thinking suggests that lifestyle patterns and environmental exposures, together known as the exposome, may help explain the rise in EOCRC. Yet identifying modifiable risk factors that are specific to EOCRC has proven difficult. Many studies compare younger patients with controls of the same age and end up pointing to the same risks already associated with late-onset colorectal cancer.
Earlier epidemiological work has linked factors such as smoking, diet, and the microbiome to colorectal cancer risk. However, those studies have faced important limits, partly because lifetime environmental exposures are hard to measure accurately. That makes it difficult to connect specific exposures clearly to cancer risk. More recent research has identified DNA methylation changes caused by particular exposures, creating new ways to study how the disease develops.
What are epigenetic marks?
Epigenetics refers to biological mechanisms that turn genes on or off without changing the DNA sequence itself. DNA methylation is one example, involving small chemical marks that attach directly to DNA.
“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,” explained José A. Seoane. “Furthermore, 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.”
“We explored the components of the exposome that might contribute to the development of colorectal cancer in young people compared to colorectal cancer diagnosed at older ages, using epigenetic markers.”
For this analysis, the investigators developed risk scores from epigenetic DNA marks (methylation) that reflect exposure to lifestyle and environmental factors. They built these scores using DNA methylation data from The Cancer Genome Atlas (TCGA) and then validated the findings in nine additional independent patient cohorts.
The investigators then compared the methylation-based risk scores in early-onset and late-onset colorectal cancer cases.
“In this analysis, we observed significant differences in epigenetic signatures associated with diet, tobacco, and pesticide exposure,” said Silvana Maas, a Postdoctoral Investigator of Seoane’s group and first author of this study. “Among the pesticides, a very clear correlation signal stood out between exposure to the pesticide picloram and early-onset colorectal cancer.”
To examine that link further, the researchers used population-based databases from the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) Program registries, along with county-level pesticide use data from the USGS Pesticide National Synthesis Project (USGC) in the United States. They found that early onset colorectal cancer incidence was significantly associated with picloram use, even after accounting for sociodemographic factors and exposure to other pesticides.
Picloram has been used as a herbicide since the mid 1960s. People currently diagnosed with LOCRC would therefore not have been exposed to it during childhood, while early onset cases may have experienced exposure across a longer portion of their lives. That longer exposure window could help explain differences in cancer development.
Picloram raises new questions
Could exposure to the herbicide picloram explain the onset of tumor development?
“Given such a clear signal, we decided to analyze the molecular characteristics of the tumors exposed to picloram in more detail,” explained Jose A. Seoane. “We observed that tumors with high exposure to the pesticide had fewer mutations in the APC gene, a key gene in colorectal cancer that regulates the Wnt pathway, which is related to cell growth. This suggests that exposure to picloram could promote cancer development even without mutations in the APC gene.”
“Further research will be necessary to confirm whether exposure to picloram is indeed behind early-onset colorectal cancer development,” he added.
Prevention moves beyond genetics
The central message of the study is that epigenetics, and methylation in particular, can serve as a way to measure environmental exposure in tissue. With this strategy, the researchers identified factors already linked to EOCRC, including diet and smoking, and also detected a new potential risk factor: the pesticide picloram, which showed a close association with this form of cancer.
“In conclusion, our findings not only provide exposome traits based on epigenetic fingerprints that could be contributing to the development of CRC, specifically in EOCRC, but also lay a solid foundation for addressing environmental exposures and lifestyle-related factors to reduce EOCRC risk, highlighting the importance of promoting preventive interventions at both the individual and public policy levels,” concluded Seoane.
Reference: “Epigenetic fingerprints link early-onset colon and rectal cancer to pesticide exposure” by Silvana C. E. Maas, Iosune Baraibar, Lea Lemler, Maria Butjosa-Espín, Odei Blanco Irazuegui, Josep Tabernero, Elena Elez and Jose A. Seoane, 21 April 2026, Nature Medicine.
DOI: 10.1038/s41591-026-04342-5
Funding received from the “la Caixa” Foundation and the Spanish Association Against Cancer
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