A Spanish study used epigenetic fingerprints to track hidden exposure patterns and found that a widely used herbicide may be linked to an alarming increase in colorectal cancer in young adults.
In a recent study published in the journal natural medicineresearchers conducted a multi-stage study to identify potential environmental exposures and lifestyle-related factors associated with the unprecedented increase in the prevalence of early-onset colorectal cancer (EOCRC).
In this study, we developed a DNA methylation-based “epigenetic fingerprint” as a surrogate for measuring exposome-related exposure patterns (termed “exposomes”) in colorectal cancer patients.
Comparing exposomes from young patients (n = 31; age <50 years) with exposomes from older patients (n = 100; age >70 years) identified the herbicide ‘picloram’ as an important new risk factor associated with EOCRC. The study then further supported this association by using an independent molecular analysis and 21 years of U.S. population data.
Taken together, these findings highlight the importance of further investigating targeted environmental health policies to reduce harmful exposures and thereby mitigate future EOCRC incidence.
Background of EOCRC and exposome hypothesis
Colorectal cancer (CRC) is a malignant tumor that affects the lining of the colon (large intestine) or rectum and currently ranks as the second leading cause of cancer-related death worldwide. CRC has historically been associated with older adults (>70 years of age). However, in recent decades, there has been a sudden and unexplained spike in the prevalence of early-onset colorectal cancer (EOCRC; colorectal cancer in patients younger than 50 years).
Surprisingly, recent studies have highlighted that EOCRC is often more aggressive and metastatic than traditional CRC at the time of diagnosis. Researchers now suspect that the ‘exposome’ – the cumulative effects of diet, lifestyle and environmental pollutants – may hold the key to explaining the rapid rise in EOCRC prevalence, but previous studies have failed to confirm this hypothesis.
This knowledge gap is believed to be due to the lack of detailed information in most traditional cancer databases about what patients may have been exposed to decades ago.
Design of epigenetic fingerprint research
The present study aimed to address this persistent knowledge gap by using DNA methylation (irreversible binding of methyl groups to DNA) as a molecular surrogate for prior exposure. These DNA methylation profiles, called “epigenetic fingerprints,” were used to reconstruct the patient’s exposure history, thereby allowing the identification of specific chemicals associated with the development of EOCRC.
The study consisted of a multi-stage investigation, with researchers first analyzing The Cancer Genome Atlas (TCGA) discovery cohort, comparing 31 younger patients (under 50 years old) to 100 older patients (over 70 years old). The findings from the discovery cohort were subsequently validated through a meta-analysis across nine independent cancer cohorts (a total of 83 EOCRC patients and 272 late-onset colorectal cancer patients).
Study analysis included the development of a new methylation risk score (MRS). These models utilize specific cytosine-phosphate-guanine (CpG) sites (previously established DNA methylation positions) as surrogates for 29 different lifestyle and environmental factors. These factors included participants’ diet, alcohol intake, smoking status, lifestyle characteristics such as BMI (n = 11), air pollution (n = 4), particularly exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5), and pesticides such as cumulative exposure to glyphosate, atrazine, and picloram (n = 14).
The association between data-derived MRS scores and environmental factors was further supported by comparing MRS with gene expression changes observed in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes exposed to various pesticides (including the pesticide under investigation). Finally, the study analyzed 21 years of population-level data from 94 U.S. counties, matching intensity of pesticide use to local colorectal cancer incidence.
The Piclorum Society and the Discovery of Molecules
Analysis of known colorectal cancer risk factors revealed that younger patients were significantly more likely to have epigenetic fingerprints associated with lower educational attainment (P = 2.11 × 10-5), smoking (P = 1.02 × 10-5), and lower adherence to the Mediterranean diet (P = 1.5 × 10-2).
However, the most striking finding of this study was the establishment of a link between ‘picloram’ (a commonly used herbicide) and EOCRC. Specifically, in the discovery cohort, high picloram MRS was strongly associated with early-onset cancer (P = 4.4 × 10-4), and the results were validated in the pooled dataset of meta-analysis (P = 1.5 × 10-2).
Furthermore, analysis of US county data revealed that higher intensity of picloram use was associated with higher incidence of colorectal cancer in young people (P = 4.52 × 10-4). These findings remained statistically significant even after adjusting the model for participants’ socio-economic variables and concurrent use of other pesticides.
Finally, molecular analysis revealed that picloram-associated colorectal cancer tumors (EOCRCs) are biologically distinct from “traditional” age-related tumors, demonstrating a lower mutation rate in the APC (adenomatous polyposis coli) gene (74% vs. 90%). Of note, this study found that Wnt/β-catenin signaling was upregulated in tumors with low picloram exposure, consistent with APC mutations, indicating that picloram-associated tumors may follow a biologically distinct pathway rather than the typical APC-associated pattern.
Taken together, these findings suggest that picloram may be associated with a diverse EOCRC molecular profile compared to that typically seen in older patients.
Environmental policy and impact on EOCRC
This study is the first to identify picloram, a herbicide commonly used in the United States since 1964, as a potentially significant environmental factor associated with EOCRC risk. The findings of this study identify generational disparities in environmental exposures between older and younger patients, which may help explain why some risk factors emerge more clearly in EOCRC.
Although this finding does not prove causation, it strengthens the case for further research into picloram and other environmental exposures as potentially modifiable causes of early-onset colorectal cancer.
