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

## TL;DR

This study explores how extra copies of chromosomes in colon cancer cells relate to tumor traits and biological pathways, suggesting a unique evolutionary state in some patients.

## Contribution

The study identifies a subset of metastatic colon cancers with polyploidy or chromosomal copy number gains and links them to specific clinicopathological and molecular features.

## Key findings

- Polyploid cells and chromosomal copy number gains are found in 25% of metastatic colon cancer cases.
- These features are more common in right-sided tumors and older patients, suggesting age-related genomic instability.
- Polyploid/CNG tumors show dysregulation in pathways related to mitosis, centrosome organization, and DNA replication stress.

## Abstract

Polyploidy and chromosomal copy number gain are characterized by the presence of extra genomic copies and may enable cancer cells to adapt and survive under conditions of biological stress. However, their role in colorectal cancer remains poorly characterized. In this study, we analyzed metastatic colon cancer samples using integrated tissue-based, cytogenetic, and DNA sequencing approaches to identify tumors harboring polyploid cells or increased gene copy numbers. We found that these features are present in a subset of patients, occurring more frequently in right-sided tumors and in older individuals, and are associated with biological pathways related to cell division and genome maintenance. Although the clinical implications of these findings remain uncertain, our results suggest that polyploidy may represent a distinct evolutionary state in colorectal cancer that merits further investigation.

Background: 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. Methods: 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. Results: 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 (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: 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.