Genetic insights into colorectal cancer pathogenesis: a multi-omics and immunity perspective.

[BACKGROUND] Colorectal cancer (CRC) is a global health issue influenced by both genetic and environmental factors. Identifying key genes closely associated with CRC is crucial for understanding its pathological mechanisms and discovering therapeutic targets. This study aimed to integrate multi-omics datasets and Mendelian randomization (MR) approaches to identify CRC-related genes and to clarify their roles in tumor immunity and therapeutic potential.

[METHODS] This is a cross-sectional study. We utilized databases such as Gene Expression Omnibus (GEO), Finnish National Genome Project (FinnGen), expression Quantitative Trait Loci (eQTL), and The Cancer Genome Atlas (TCGA), and employed MR, summary-data-based MR (SMR), and gene expression analyses to screen genes related to CRC development. Through immune cell infiltration analysis and mediation MR, we explored the relationship between these genes, tumor immunity, and immunotherapy.

[RESULTS] Our study identified and as risk factors for CRC, while and were found to be protective factors. Additionally, the differential expression of these genes in CRC tissues was validated through immunohistochemistry (IHC) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) experiments. Mediation MR analysis demonstrated that immune cell phenotypes could mediate the effect of these genes on CRC. These genes were also found to be associated with tumor mutational burden (TMB) and microsatellite instability (MSI) scores.

[CONCLUSIONS] Our findings reveal how these genes contribute to CRC pathogenesis by modulating the immune microenvironment, providing important biomarkers and targets for the development of novel therapeutic strategies.