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

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.