Study links common herbicide to rising early-onset colorectal cancer risk

In a recent study published in the journal Nature Medicine, researchers conducted a multi-phase investigation to identify potential environmental exposures and lifestyle-related factors associated with unprecedented increases in the prevalence of early-onset colorectal cancer (EOCRC).

The study developed DNA methylation-informed “epigenetic fingerprints” as proxies for measuring colorectal cancer patients’ exposome-related exposure patterns (termed the “exposome”).

Comparing the exposomes of young patients (n = 31; age <50 years) with those of older patients (n = 100; age ≥70 years) identified the herbicide “picloram” as a significant new risk factor associated with EOCRC. The study subsequently provided additional support for this association through independent molecular analysis and by using 21 years of US population data.

Together, these findings highlight the importance of further investigating targeted environmental health policies to reduce harmful exposures and thereby mitigate future EOCRC incidence.

EOCRC Background and Exposome Hypothesis

Colorectal cancer (CRC) is a malignancy afflicting the inner 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 age (≥70 years); however, recent decades have witnessed a sudden and inexplicable surge in the prevalence of early-onset colorectal cancer (EOCRC; CRC in patients <50 years).

Alarmingly, recent studies highlight that EOCRC is often more aggressive and metastatic at diagnosis than traditional CRC. Researchers now suspect that the “exposome”, the cumulative effect of diet, lifestyle, and environmental pollutants, might hold the key to elucidating EOCRC’s prevalence surge, but hitherto, studies have failed to confirm this hypothesis.

This knowledge gap has been attributed to the lack of detailed information in most conventional cancer databases about what a patient may have been exposed to decades ago.

Epigenetic Fingerprint Study Design

The present study aimed to address this persistent knowledge gap by using DNA methylation, the irreversible attachment of methyl groups to DNA, as a molecular proxy of prior exposure. Termed “epigenetic fingerprints”, these DNA methylation profiles were used to reconstruct patients’ exposure histories, thereby enabling the identification of specific chemicals associated with EOCRC incidence.

The study comprised a multi-phase investigation in which researchers first analyzed a discovery cohort from The Cancer Genome Atlas (TCGA), comparing 31 young patients (<50 years) with 100 older patients (≥70 years). Findings from the discovery cohort were subsequently verified through a meta-analysis across 9 independent cancer cohorts (83 EOCRC and 272 late-onset colorectal cancer patients in total).

The study analyses included the development of novel Methylation Risk Scores (MRS). These models leverage specific cytosine-phosphate-guanine (CpG) sites (previously established locations of DNA methylation) as proxies for 29 different lifestyle and environmental factors. These factors included lifestyle traits (n = 11), including participants’ diet, alcohol consumption, smoking status, and body mass index (BMI), air pollution (n = 4), particularly nitrogen dioxide (NO2) and particulate matter (PM2.5) exposure, and pesticides (n = 14), including cumulative glyphosate, atrazine, and picloram exposure.

The association between the data-derived MRS scores and environmental factors was further supported by comparing MRS against gene expression changes observed in human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes exposed to various pesticides (including those under investigation). Finally, the study analyzed 21 years of population-level data from 94 US counties, matching pesticide use intensity with local colorectal cancer incidence rates.

Picloram Association and Molecular Findings

Analyses of known CRC risk factors revealed that young 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 a Mediterranean diet (P = 1.5 × 10-2).

However, the study’s most striking finding was the establishment of a link between “picloram” (a commonly used herbicide) and EOCRC. Specifically, in the discovery cohort, a high picloram MRS was strongly associated with early-onset cancer (P = 4.4 × 10-4), a result that was validated in the meta-analyses’ pooled dataset (P = 1.5 × 10-2).

Furthermore, analyses of US county data revealed that higher picloram use intensity was associated with higher rates of colorectal cancer in young people (P = 4.52 × 10-4). These findings remained statistically significant even after adjusting the models for participants’ socioeconomic variables and the concurrent use of other pesticides.

Finally, molecular analyses revealed that picloram-linked CRC tumors (EOCRC) were biologically distinct from their ‘traditional’ age-associated counterparts, demonstrating a lower rate of mutations in the APC (Adenomatous Polyposis Coli) gene (74% vs. 90%). Notably, the 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-linked pattern.

Together, these findings suggest that picloram may be associated with a divergent EOCRC molecular profile compared with that typically seen in older patients.

Environmental Policy and EOCRC Implications

The present study is the first to identify picloram, a commonly used herbicide in the US since 1964, as a potentially critical environmental factor associated with EOCRC risk. The findings identified a generational divide in environmental exposures between older and younger patients, which may help explain why some risk factors are emerging more clearly in EOCRC.

While the findings do not prove causation, they strengthen the case for further research into picloram and other environmental exposures as potentially modifiable contributors to early-onset colorectal cancer.