The World Health Organization cites colorectal cancer (CRC) as the second leading cause of cancer-related deaths worldwide. Although it predominantly affects individuals aged 50 and above, the risk to those under the age of 50—otherwise known as early-onset CRC—is increasing. Early-onset CRC is thought to have distinct pathophysiological features and risk profile; however, relatively little is known about the factors driving the increases in incidence rates. In this context, Silvana Maas and colleagues recently published a study in Nature Medicine exploring potential risk factors using epigenetic profiling. The study validated identified risk factors, including educational attainment, diet, and tobacco use. Crucially, they identified exposure to the pesticide picloram as a new potential risk factor.
The team studied US population data from 94 counties over 21 years to look at environmental exposures linked to the process of DNA methylation. Unlike genetic mutations, which alter the DNA sequence, processes like methylation add signatures onto the DNA that alter the expression of genes. This process can occur in response to exposures in everyday life, such as smoking, and is thought to be implicated in the development of cancer. The authors developed methylation risk scores that reflected patterns of DNA methylation related to specific exposures, including several pesticides. In statistical models, they compared the methylation risk scores of those with early-onset CRC (ages <50 years) to those with late-onset (ages ≥70 years), using four thresholds of statistical significance to test the strength of association. The study identified factors already commonly implicated in CRC risk, including tobacco use, diet, body mass index (BMI), and educational attainment. Notably, they found that higher methylation risk scores related to picloram exposure were more commonly associated with early-onset CRC (when compared to late-onset) at every threshold of significance. These findings also held when replicated in other participant cohorts. This is particularly striking given that picloram entered widespread use as a pesticide in the mid-1960s, and therefore, those with late-onset CRC would not have been exposed to it in early life.
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The study provides a compelling case of how methylation risk scores can be used to quantify environmental factors, which are otherwise difficult to capture objectively. GlobalData epidemiologists forecast that incident cases of early-onset CRC across 16 major markets (16MM: Australia, Brazil, Canada, France, Germany, India, Italy, Japan, Mexico, Russia, South Africa, South Korea, Spain, UK, US, and urban China) will increase from 122,000 cases in 2026 to 128,000 by 2031. Although these findings are not proof of causality, they provide a promising lead in the fight against CRC.
