MSH2 in colorectal cancer: A comprehensive review of molecular mechanisms, clinical prognosis, and a precision oncology framework.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with genetic alterations playing critical roles in tumor development and patient outcomes. Among the genetic alterations, mutations in the MSH2 gene, a key component of the DNA mismatch repair system, garner significant attention for their influence on CRC pathogenesis and prognosis. This review synthesizes current research centered on whole genome sequencing (WGS) technologies that enable comprehensive characterization of MSH2 mutations and their molecular underpinnings. We examine the spectrum of MSH2 mutation types identified by WGS, their impact on tumor microenvironment modulation, therapeutic response variability, and patient survival rates. Despite advances, challenges remain in fully elucidating the prognostic value of MSH2 mutations because tumor heterogeneity leads to variable mutation expression across tumor cells, and complex gene-environment interactions influence how these mutations affect disease progression and treatment outcomes. By integrating multiple WGS datasets from different cohorts, this review first highlights the role of data integration in enhancing the robustness of findings. It then discusses the potential of MSH2 mutations as robust prognostic biomarkers and their emerging role in guiding personalized treatment strategies for CRC. Based on this synthesis, we propose a novel clinical decision-making framework that leverages MSH2 status to stratify patients, optimize immunotherapy selection, and enable dynamic monitoring through circulating tumor DNA (ctDNA) profiling. This framework represents a practical tool for translating genomic insights into precision oncology practice. These findings, including the characterization of MSH2 mutation types, their biological impacts, and clinical applications, underscore the promise of leveraging genomic insights to enhance precision oncology approaches and improve clinical outcomes for CRC patients.