Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications

Simple Summary Metastatic colorectal cancer is a complex, prevalent, and life-threatening disease influenced by various factors that affect its progression, evolution, and treatment responses. Tumor heterogeneity, stemming from genetic and non-genetic factors, impacts tumor development and therapy effectiveness. This feature can be assessed by computational analysis of next-generation sequencing to understand spatial tumor evolution and diversity. Analyzing circulating tumor DNA allows the study of temporal heterogeneity by real-time monitoring of tumor changes and treatment response. Different models explain the origins of this heterogeneity, emphasizing complex molecular pathways. This review examines these concepts and focuses on the clinical implications of clonal evolution and tumor heterogeneity.Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.