Epigenetic Exposure Signatures Distinguish Early-Onset from Later-Onset Colorectal Cancer in a Racially Diverse US Cohort: Findings from the Disparities and Cancer Epidemiology (DANCE) Study

Background: The incidence of early-onset colorectal cancer (EOCRC), defined as CRC diagnosed age <50, is rising in the United States and is the leading cause of cancer death in among those with early-onset cancer. Epigenetic exposure signatures based on methylation risk scores (MRS) offer a novel approach to identify long-term exposures that may contribute to EOCRC risk. We sought to replicate findings from a recent study in a racially and geographically diverse CRC cohort. Methods: We computed weighted MRS across lifestyle, air pollution, and pesticide exposome traits in 146 participants from the Disparities and Cancer Epidemiology (DANCE) cohort, a diverse population-based CRC study, applying the Maas et al. (2026) framework to tumor tissue. Associations between MRS and age at CRC onset (EOCRC, n=29; intermediate-onset (IOCRC) 50-64 years, n=69; late-onset, [&ge;]65 years, n=48) were evaluated using linear and polytomous regression, with adjustment and stratification for race, geography, Area Deprivation Index (ADI), and Multi-Environmental Exposure Index (MEEI). Spearman correlations were calculated between MRSes and observed exposures. Results: EOCRC cases were predominately Black (65.5% vs. 31.3% among LOCRC) and resided in higher-deprivation neighborhoods. We found higher odds of EOCRC associated with epigenetic exposure signatures for 2,4-D herbicide, heptachlor, coarse particulate matter (PM), Mediterranean Diet Score, and smoking, and borderline associations for fine PM and nitrogen dioxide. IOCRC was associated with signatures for 2,4-D, lindane, and obesity. Heterogeneity was observed by race and area-level factors, though associations were largely consistent across strata. ADI and MEEI were correlated with multiple pesticide and pollutant epigenetic signatures. Conclusions: In a diverse US cohort, epigenetic exposure signatures distinguish CRC cohorts, particularly EOCRC from later-onset disease, with associations consistent with but not identical to previous research. EOCRC in DANCE was characterized by higher epigenetic exposure signatures for air pollution, smoking, and distinct pesticide exposure profiles. IOCRC had overlapping characteristics with early- and late-onset and were the only group with a significant obesity signature. These findings support the hypothesis that exposome-driven epigenetic changes contribute to EOCRC risk and highlight the importance of studying diverse populations to characterize the full spectrum of environmental risk factors.