Epigenetic fingerprints link early-onset colon and rectal cancer to pesticide exposure.

The incidence of colorectal cancer (CRC) is rising rapidly in people younger than 50 years. Although this increase parallels shifts in lifestyle and environmental factors-collectively termed the exposome-whether these are indeed linked to the development of early-onset CRC (EOCRC) remains uninvestigated. Due to limited exposome data in most cancer cohorts, we constructed weighted methylation risk scores as proxies for exposome exposure to pinpoint specific risk factors associated with EOCRC compared to late-onset CRC (LOCRC) patients diagnosed at ≥70 years. Our analysis confirmed previously identified risk factors, including educational attainment, diet and smoking habits. Moreover, we identified exposure to the herbicide picloram as a new risk factor (adjusted P = 4.4 × 10-4) in the discovery cohort (31 EOCRC versus 100 LOCRC), which was replicated in a meta-analysis comprising nine CRC cohorts (P = 3.1 × 10-3; adjusted P = 1.5 × 10-2; 83 EOCRC versus 272 LOCRC). Subsequently, we analyzed population-based data from 94 US counties over 21 years and validated the association between picloram use and EOCRC incidence (P = 4.52 × 10-4), which remained significant after adjusting for socioeconomic factors and other pesticide use. These findings highlight the critical role of the exposome in EOCRC risk, underscoring the urgency for targeted personal and policy-level interventions.