Abstract PR002: Clinical, pathological, and molecular differences in early- and late-onset colorectal cancer: Results from a multicenter study

Abstract Introduction: The incidence of colorectal cancer (CRC) in individuals under 50, referred to as early-onset colorectal cancer (EO-CRC), has risen markedly in recent decades. By 2030, EO-CRC is projected to account for 10. 9% of colon and 22. 9% of rectal cancers. By contrast, cases diagnosed at ≥50 years are classified as late-onset CRC (LO-CRC), corresponding to the population historically included in routine screening. Because routine screening is not offered to younger adults, EO-CRC is often detected at advanced stages, underscoring the need for tailored prevention and detection strategies. In this study, we investigated clinical, pathological, and molecular differences between EO-CRC and LO-CRC, focusing on stage distribution, tumor location, and DNA methylation profiles, and evaluated the association of age with CRC and adenoma risk. Methods: From 2018 to 2024, a total of 12, 520 individuals were enrolled in a multicenter trial conducted in Spain and the United States. The cohort included 4, 977 controls, 1, 731 with non-advanced adenomas, 2, 244 with advanced adenomas, and 3, 568 with CRC. Most participants were recruited through average-risk screening colonoscopies (either first-time or surveillance after negative screening, including FIT-based programs), with additional enrollment of EO-CRC cases. For CRC patients, the distribution of tumors by stage and location was assessed. Odds ratios (ORs) were estimated to determine adenoma and CRC risk EO-CRC and LO-CRC. DNA methylation was analyzed by comparing average methylation frequency (AMF) between groups using the Mann-Whitney U test. Results: A total of 140 CRC cases were diagnosed in patients 50 years versus 3, 428 in ≥50. EO-CRC patients more frequently presented with stage IV disease (22. 8% vs. 12. 1% in LO-CRC). Tumor distribution also differed significantly by age: EO-CRC was more often located in the distal colon (54. 5% vs. 39. 4% in LO-CRC) and rectum (23. 6% vs. 19. 2%), whereas LO-CRC was predominantly proximal (39. 8% vs. 22. 0% in EO-CRC). No significant association was found between age 50 and advanced adenomas (OR 0. 94, p=0. 54). CRC risk increased progressively with age (OR 1. 24 at 50–59 to OR 3. 88 at 80–89). Nevertheless, individuals 50 years had 22% higher odds of CRC compared with older groups (OR 1. 22). Methylation analyses revealed significantly higher EO-CRC AMF values than age-matched controls (p=9. 2e-03), with more substantial differences than those observed in LO-CRC. Conclusion: CRC risk escalates with age, yet EO-CRC is disproportionately diagnosed at advanced stages and in distal/rectal sites. Younger patients also display distinct methylation alterations, supporting a divergent tumor biology. These findings highlight the need for heightened awareness, refinement of risk stratification, and consideration of earlier screening or molecular-based surveillance in younger populations. Citation Format: NASTARAN Riahi Dehkordi, Carme D. Nolla Colomer, Francesco D. Mattia Mancuso, Kristi Kruusmaa. Clinical, pathological, and molecular differences in early- and late-onset colorectal cancer: Results from a multicenter study 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 (23Suppl): Abstract nr PR002.