A paradigm shift in genetic predisposition to colorectal cancer: the impact of germline multigene panel testing on diagnosis and management.

Hereditary colorectal cancer (HCRC), arising from pathogenic germline variants, accounts for 5-10% of all CRCs. The widespread clinical adoption of next-generation sequencing (NGS) and multigene panel testing (MGPT) has fundamentally transformed the diagnostic paradigm for this genetic predisposition. This review summarizes the latest epidemiological data on genetic predisposition to CRC and examines the essential practical changes required for genomics-based precision medicine. Recent large-scale genomic cohort studies have consistently revealed a higher prevalence of pathogenic/likely pathogenic germline variants (PGVs) in unselected CRC populations than previously recognized, ranging from 3.3 to 15.5%. This proportion is dramatically elevated in patients with early onset CRC (EOCRC), defined as a diagnosis before age 50, where prevalence consistently exceeds 15%. Notably, MGPT has expanded the etiological spectrum far beyond Lynch syndrome (LS)-related genes, demonstrating a significant contribution from non-LS and high- and moderate-penetrance genes, particularly those associated with homologous recombination deficiency (HRD). Consequently, the management of genetic predisposition to CRC is rapidly shifting from single syndrome-based diagnoses to individualized precision medicine guided by gene-specific lifetime cancer risks. To realize clinical benefits, two imperatives must be addressed: (1) the implementation of universal genomic screening for all patients with EOCRC and (2) the development of proactive medical-contact approach models in cascade screening for at-risk relatives. Nevertheless, the viability of this proposal varies considerably between Europe, America, and Asia. Considerable uncertainty surrounds implementation in Asia, where a plethora of challenges must be overcome to facilitate the integration of genomic medicine within the Asian context.