Identification of novel protein markers and therapeutic targets for common urological cancers by integrating large-scale human plasma proteome with the genome

Considering that the circulating proteome represents a primary source of candidate biomarkers and therapeutic targets, we conducted a large-scale Mendelian randomization (MR) study to identify plasma proteins potentially involved in the pathogenesis and treatment of common urological cancers (UCs), including bladder cancer (BC), prostate cancer (PC), renal cell carcinoma (RCC), and testicular cancer (TC). Cis-protein quantitative trait loci (cis-pQTLs) were derived from two large-scale genome-wide association studies (GWASs) of plasma proteomes. GWAS for UCs were obtained from FinnGen and pan-UKBB meta-analysis, FinnGen and UK Biobank. Colocalization analysis and summary data-based MR (SMR) were performed to evaluate the robustness of the associations. Further evaluations involved Bulk RNA-seq differential expression and single cell-type expression analysis, protein–protein interaction, and druggability evaluation. For BC, we identified four protein markers: one associated with increased risk (PSCA) and three with decreased risk (GSTM1, GSTM3, GSTM4), which are mainly expressed in pericyte, urothelial, and NK cells in bladder tumors. Regarding PC, we found 15 protein markers: seven linked to increased risk (AGER, ALAD, CHMP2B, PEX14, ZG16B, PPP1R14A, SERPINA3) and eight to decreased risk (BTN2A1, CEACAM21, DNAJB9, MSMB, PYGL, HLA-E, SOD2, TOR1AIP1), enriched in epithelial cells, monocytes/macrophages in prostate tumors. The strongest evidence from MR and colocalization analyses supported GSTM4 (BC), SOD2 and CHMP2B (PC) as causal markers. Notably, seven identified proteins have been previously targeted by drugs for other cancers and immune disorders, indicating their potential therapeutic relevance in UCs. This study highlights several proteins with predictive value for BC and PC risk and supports their utility in biomarker discovery and drug development.