Oligometastatic versus polymetastatic colon cancer: functional and genomic determinants of divergent metastatic trajectories

Aim: The aim of this study is to investigate the molecular and functional features underlying the clinical heterogeneity between oligometastatic (OM) and polymetastatic (PM) colon cancer. Methods: We performed a genotype-phenotype analysis in a homogeneous cohort of 127 patients with metastatic colon cancer (mCC) profiled using the same next-generation sequencing platform (TruSight Oncology® 500). OM disease was defined as the presence of one to three metastatic lesions per involved organ, involving no more than two organs overall, with all lesions measuring < 70 mm in maximum diameter and no single lesion > 25 mm. Molecular alterations, microsatellite instability (MSI), tumor mutational burden (TMB), and overall survival (OS) were analyzed. Gene Ontology (GO) enrichment and Phenolyzer network analyses were applied to explore functional differences between prognostically distinct molecular subgroups. Results: OM patients showed a striking survival advantage compared with PM patients [median OS not reached versus 29 months; hazard ratio (HR): 0.20, P < 0.0001], validating the clinical distinction between the two phenotypes. PM disease was significantly enriched for RAS mutations, whereas OM disease was associated with MSI-high status and elevated TMB. Canonical driver alterations were largely shared between groups, and Phenolyzer analysis revealed similar core oncogenic networks centered on adenomatous polyposis coli (APC), tumor protein p53 (TP53), and epidermal growth factor receptor (EGFR). In contrast, GO analysis demonstrated selective enrichment in PM tumors for molecular functions related to ATP binding, nucleotide binding, and protein kinase activity, consistent with enhanced bioenergetic demand and signaling intensity. Conclusions: These findings support refined biological stratification of mCC and the exploration of personalized, metastasis-directed strategies, potentially incorporating immunological modulation in OM disease.