Colorectal Cancer: Epidemiology, Risk Factors, Signaling Pathways, Clinical Features, Screening, Diagnosis, and Management

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer incidence and mortality worldwide and is increasingly characterized by two converging realities: a substantial global burden and a rising incidence of early‐onset CRC. This review synthesizes current advances in CRC epidemiology, risk factors, signaling biology, clinical presentation, screening, diagnosis, and management across the care continuum. We frame CRC as a systems‐level disease in which genomic instability, epigenetic dysregulation, metabolic remodeling, tumor microenvironmental evolution, and gut microbiota interactions converge on interconnected pathways, including Wnt/β‐catenin, MAPK, PI3K/AKT/mTOR, TGF‐β, and immune‐regulatory networks. We distinguish established standards of care from recent practice‐changing developments and investigational strategies. Within this framework, we discuss blood‐based screening, AI‐assisted endoscopy, ctDNA‐informed residual disease assessment, biomarker‐defined molecular workup, immunotherapy strategies for dMMR disease, and targeted approaches for KRAS G12C‐mutated, BRAF V600E‐mutated, and HER2‐positive metastatic CRC. Despite substantial progress, major challenges remain, including limited immunotherapy benefit in microsatellite‐stable CRC, unequal access to high‐quality screening and molecular testing, and uncertainty regarding implementation of newer biomarkers across diverse populations. An integrated framework linking population risk, tumor ecology, evidence‐based biomarker use, and equitable precision care is essential for the next phase of CRC prevention and management.