Early-Onset Colorectal Cancer: Epidemiology, Molecular Drivers, and Implications for Screening and Treatment

Abstract

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before age 50, has become a rapidly increasing global health concern. In contrast to declining rates in older adults, EOCRC incidence has nearly doubled in several high-income countries since the early 1990s and is rising in more than half of countries worldwide, particularly among individuals born after the 1960s, reflecting a clear birth‑cohort effect. In the United States, colorectal cancer is now the leading cause of cancer-related death in men under 50 and the second leading cause in women of the same age. Although hereditary syndromes such as Lynch syndrome and familial adenomatous polyposis account for 16--20% of cases, most EOCRC is sporadic and linked to environmental exposures, lifestyle factors, gut microbiome dysbiosis, and early‑life influences. EOCRC displays distinct molecular features compared with late-onset disease, including lower frequencies of BRAF and KRAS mutations, higher rates of microsatellite instability-high tumors outside hereditary contexts, and enrichment of TP53 and CTNNB1 alterations. Clinically, EOCRC often presents at advanced stages, shows rectal predominance, and is associated with diagnostic delays of up to six months due to misattribution of symptoms to benign conditions. In response to rising incidence, major U.S. guidelines now recommend initiating colorectal cancer screening at age 45. Treatment increasingly incorporates immunotherapy for mismatch repair-deficient tumors, with neoadjuvant PD‑1 blockade producing exceptional pathological complete response rates. This review summarizes current evidence on EOCRC epidemiology, biology, clinical presentation, screening, and treatment, and highlights emerging directions including liquid biopsy, artificial intelligence, and microbiome-based strategies.