PhD Scientific Days 2026

Pathological and Oncological Sciences 2.

Investigation of Genomic Instability Mechanisms in Colorectal Cancer

Name of the presenter

Csőke, Dávid

Institute/workplace of the presenter

Department of Pathology, Forensic and Insurance Medicine Semmelweis University, Faculty of Medicine

Authors

Dávid Csőke¹, Dr. Tamás Barbai¹
1: Department of Pathology, Forensic and Insurance Medicine Semmelweis University, Faculty of Medicine

Text of the abstract

Introduction
Approximately 15% of colorectal tumors exhibit high microsatellite instability (MSI-H) genotype, which is associated with genomic instability and increased neoantigen formation. This phenotype is primarily linked to defects in the mismatch repair (MMR) system, driven by pathogenic variants in genes involved in DNA repair pathways, in addition to mutations affecting known oncogenes and tumor suppressor genes. However, it remains an open question whether dysfunction of this single genomic system alone is sufficient to drive the development of the MSI-H phenotype.
Aims
The aim of our study was to characterize genetic patterns across MSI-H, MSI-intermediate (MSI-I), and microsatellite-stable (MSS) tumors, with particular emphasis on determining the distribution of clinically relevant pathogenic variants within each group.
Methods
DNA sequencing was performed on samples isolated from gastrointestinal-origin solid tumors using the Oncomine Comprehensive Assay panel. Samples were pre-classified based on microsatellite instability status.
Results
Across all groups, we identified 63 variants present in each category, from which differences in allele frequency and occurrence patterns could be inferred. Additionally, 8 variants were detected exclusively in the MSS and MSI-I groups with varying prevalence. Based on pathogenicity classification, variants were categorized as follows: 2 benign, 6 likely benign, 11 likely pathogenic, 3 pathogenic, and 49 variants of uncertain significance (VUS).
Conclusion
Our findings indicate that MSI-H tumors, beyond harboring known pathogenic variants and MMR pathway alterations, exhibit a higher prevalence of mutations affecting the HRR pathway. In contrast, MSI-I tumors predominantly carry likely pathogenic and likely benign variants within MMR-related genes. No significant differences were observed in the mutation profiles of established oncogenes and tumor suppressor genes across the groups.
These results suggest that genomic instability in colorectal cancer is not solely driven by MMR deficiency but rather arises from a complex interplay involving concurrent defects in multiple DNA repair pathways, ultimately contributing to the development of the MSI-H phenotype.
Funding
This research was funded by the Semmelweis University Doctoral College Grant.