Polyploid and Chromosomal Copy Number Gain Cells in Metastatic Colon Cancer: Exploratory Genotype–Phenotype Correlations

<b>Background:</b> Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. <b>Methods:</b> We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. <b>Results:</b> Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (<i>RAS</i>, <i>TP53</i>, <i>SMAD4</i>), although trends toward co-occurrence with <i>BRAF</i> mutation and mutual exclusivity with <i>HER2</i> amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. <b>Conclusions:</b> In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification.