Early-onset colorectal cancer: a comprehensive review reframing hypotheses and defining research priorities

PURPOSE: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before the age of 50 years, is increasing worldwide and represents a growing clinical and public health challenge. Whether EOCRC constitutes a biologically distinct entity remains uncertain, and current diagnostic and therapeutic strategies are largely extrapolated from late-onset disease. METHODS: This narrative review summarizes recent evidence on EOCRC biology, diagnosis, and management, focusing on molecular and genomic features, tumor microenvironment, exposome-related factors, diagnostic pathways, treatment paradigms, and emerging strategies for early detection. We critically examine the gap between biological insights and real-world clinical practice and outline priorities for future research. RESULTS: EOCRC displays a heterogeneous molecular landscape that substantially overlaps with late-onset colorectal cancer. Although advances in multiomics profiling, liquid biopsy, and microbiome research have improved biological understanding, these findings have not yet translated into EOCRC-specific diagnostic or therapeutic approaches. Diagnosis remains delayed due to age-based screening paradigms and symptom misattribution, resulting in advanced-stage presentation. Younger patients frequently receive intensified treatment despite limited age-specific evidence and insufficient attention to long-term toxicity, fertility, and survivorship. CONCLUSION: EOCRC underdiagnosis is likely multifactorial. While limitations in biological knowledge and diagnostic tools may play a role, the discrepancy between current paradigms and the age-specific risk profiles of younger patients likely represents an important contributing factor. Progress will require biology-informed, risk-adapted screening strategies and EOCRC-focused clinical research.