The Molecular Signature of Early-Onset Colorectal Cancer Liver Metastases: Distinct Biology and Clinical Challenges

Early-onset colorectal cancer (EOCRC), defined as diagnosis before the age of 50 years, is increasing globally and is frequently characterized by aggressive biology and a disproportionate burden of liver metastases. This review synthesizes emerging evidence on the distinct molecular, immunologic and clinical features that differentiate EOCRC liver metastases from those arising in older adults. Genomic studies revealed increased chromosomal instability, increased copy number variation burden and unique amplification patterns involving MYC, RAD21, GNAS and MAPK1, alongside altered frequencies of classical driver mutations and increased germline predisposition. EOCRC liver metastases also exhibit a progenitor-like transcriptional state and an immune-cold microenvironment marked by reduced myeloid infiltration, impaired antigen presentation and profound resistance to immunotherapy, particularly in microsatellite-stable disease. Mechanistic insights into ferroptosis highlight therapeutic vulnerabilities, especially in PIK3CA-mutant tumors, where aspirin and ferroptosis inducers show synergistic potential. Clinically, high-risk EOCRC patients often present with left-sided primary tumors, synchronous metastases, adverse histology, elevated CEA levels and a hereditary predisposition, with prognostic models incorporating these variables outperforming traditional staging. Collectively, accumulating evidence suggests that EOCRC liver metastases may represent a biologically and clinically distinct entity, although ongoing debates regarding the extent of this distinction underscore the need for age-specific molecular profiling and prospectively validated therapeutic strategies.