Abstract PR003: Exploring the exposome impact in early-onset colon and rectal cancer using methylation scores

The incidence of early-onset colorectal cancer (eoCRC) has risen worldwide, yet the drivers of this trend remain poorly understood. Directly investigating the exposome as a possible risk factor has been hindered by limited data availability, particularly beyond standard lifestyle factors, such as an unhealthy diet and smoking. To enable the study of a greater variety of exposome factors, we investigated the possibility of using DNA methylation as an indirect biomarker for the exposome. We derived methylation scores (MSs) for 29 exposures, including lifestyle, air pollution, and pesticides, based on published epigenome-wide association studies. These MSs were used to compare eoCRC and later-onset CRC (loCRC) tumors in The Cancer Genome Atlas (TCGA) Colon Adenocarcinoma cohort (31 eoCRC vs. 100 loCRC), followed by replication through meta-analysis across nine independent studies (83 eoCRC vs. 272 loCRC). For exposures within the selected 29 factors where direct measurements were available, MSs consistently reflected associations with measured exposures in tumor or blood profiles. Moreover, our approach successfully identified established risk factors for eoCRC, such as lower educational attainment, smoking, and non-Mediterranean dietary patterns, further validating the proposed methodology. Besides validating our proposed methodology, we identified picloram, an herbicide classified as IARC Group 3, as a potential novel risk factor. To address the limited methylation data on picloram, we integrated transcriptomic profiles from pluripotent stem cell–derived cardiomyocytes exposed to picloram. Differentially expressed genes under exposure were used to construct a picloram-specific single-sample GSEA (ssGSEA) score in TCGA-COAD, which showed significant correlation with the picloram-MS. At the population level, we further linked U.S. county-level eoCRC incidence from the SEER program to picloram application estimates (NAWQA Project, 1992–2012). This relationship remained significant after adjusting for socioeconomic indicators and other pesticide use. Together, these findings demonstrate the utility of MSs as effective proxies in exposome research and demonstrate their ability to uncover novel environmental risk factors. Beyond confirming known contributors, our study highlights picloram as a candidate exposure associated with eoCRC, supported by evidence across methylation, transcriptomic, and population data. These results underscore exposome differences between eoCRC and loCRC and suggest opportunities for prevention through exposome modification and regulatory policy. Citation Format: Silvana C.E. Maas, Iosune Baraibar, Lea Lemler, Maria Butjosa-Espín, Odei Blanco Irazuegui, Josep Tabernero, Elena Elez, Jose A. Seoane. Exploring the exposome impact in early-onset colon and rectal cancer using methylation scores [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR003.