Integrative genomic and single-cell framework identifies druggable targets for colorectal cancer precision therapy

作者：Yanggang Hong, Jiajun Li, Nuo Xu, Wanyi Shu, Feng Chen, Yuze Mi, Haigang Geng, Qian Li · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1604154 · 被引用次数：16 · 研究领域：Ferroptosis and cancer prognosis、Single-cell and spatial transcriptomics、Genetic Associations and Epidemiology

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Despite therapeutic advances, there is a critical need to identify novel, effective, and safe drug targets to improve precision treatment strategies. Methods: We developed a multi-layered framework integrating Mendelian randomization (MR), colocalization analysis, genome-wide association study (GWAS) data, and expression quantitative trait loci (eQTLs) to prioritize causal and druggable genes in CRC. Single-cell and bulk RNA sequencing were used to characterize gene expression within the tumor microenvironment. Phenome-wide association studies (PheWAS) assessed off-target effects, and drug repurposing potential was evaluated using OpenTargets, DrugBank, and DGIdb. Validation of key targets was performed through RT-qPCR and immunohistochemistry (IHC) in CRC patient samples. Results: Out of 4,479 druggable genes, MR analysis identified 47 candidates significantly associated with CRC risk. Six genes (TFRC, TNFSF14, LAMC1, PLK1, TYMS, and TSSK6) demonstrated strong colocalization signals and were further validated across replication datasets and subtype-stratified analyses. PheWAS analysis revealed minimal off-target effects for these genes. Notably, several of these genes have already been targeted by existing or investigational drugs, suggesting potential for repurposing. These genes exhibited distinct expression patterns in tumor and stromal cell types and were differentially exp...