Maurizio Capuozzo, Carmine Picone, Francesco Sabbatino, Mariachiara Santorsola, Francesco Caraglia, Domenico Iervolino, Roberto Sirica, Oreste Gualillo, Giordana Di Mauro, Rosa Castiello, Monica Ianniello, Alessia Maria Cossu, Angela Nebbioso, Lucia Altucci, Francesco Izzo, Renato Patrone, Andrea Belli, Massimiliano Berretta, Marco Cascella, Francesco Perri, Anna Chiara Carratù, Guglielmo Nasti, Massimo Di Maïo, Antonio Giordano, Giovanni Savarese, Michele Caraglia, Alessandro Ottaiano
Colorectal cancer (CRC) is among the most prevalent malignancies worldwide, representing the second leading cause of cancer-related mortality and accounting for approximately 2 million new cases and nearly half a million deaths annually. Global age-standardized incidence rates are highest in Australia/New Zealand and other Western countries, and lowest in parts of sub-Saharan Africa and South Asia, reflecting variations in demographics, lifestyle exposures, and screening practices. Colon cancer constitutes the larger fraction of CRC cases, with rectal cancer contributing substantially, and early-onset CRC (<50 years) is increasing across both high-income and emerging regions. Established risk factors include age, hereditary syndromes, obesity, sedentary behavior, dietary patterns, metabolic disorders, and chronic inflammation, with notable distinctions between colon and rectal subsites. This narrative review provides a comprehensive overview of CRC epidemiology, molecular and genetic pathogenesis, staging, and modern therapeutic approaches, addressing colon and rectal cancers separately due to their distinct biology, clinical behavior, and treatment strategies. By integrating current knowledge on genetic drivers, systemic and local therapies, and patient stratification, the review aims to inform clinical practice, support clinical trial design, discuss ongoing challenges and future perspectives, and foster further research toward precision-guided management of CRC.