Early-Onset Colorectal Cancer: Molecular Features, Risk Stratification, Screening Gaps, and Personalized Prevention

Although overall colorectal cancer (CRC) incidence and mortality have declined with widespread screening, early-onset CRC (EOCRC), defined as diagnosis before age 50, continues to rise. EOCRC partially differs from late-onset CRC (LOCRC) in clinical presentation, molecular features, polyp characteristics, and patterns of modifiable risk factors; however, the extent to which these differences reflect distinct underlying biology remains uncertain. Despite updated recommendations from the 2018 American Cancer Society and 2021 U.S. Preventive Services Task Force to initiate average-risk screening at age 45, fewer than 21% of eligible adults aged 45–49 years old were up to date with screening in 2021, highlighting a substantial gap in uptake. Emerging data on epidemiologic patterns, molecular features, and risk modifiers offer opportunities to refine personalized risk prediction tools and optimize early detection. This review synthesizes current evidence on EOCRC biology and risk factors, evaluates evolving screening guidelines across professional societies, and examines barriers to screening, including access disparities, limited awareness, and psychosocial factors, thus emphasizing the urgent need to improve implementation and risk-based prevention strategies.