PLASMA protein biomarkers identified through Mendelian randomisation analysis reveal significant insights into urological cancer risk and therapeutic targeting across multiple tumour types.
Plasma Protein Biomarkers in Urological Cancer
The circulating proteome represents a key source of candidate biomarkers and therapeutic targets, prompting researchers to conduct a large-scale Mendelian randomisation study to investigate common urological cancers.
These included bladder cancer, prostate cancer, renal cell carcinoma, and testicular cancer. Cis protein quantitative trait loci derived from two genome wide association studies of plasma proteomes were used, alongside genetic data from FinnGen and UK Biobank cohorts.
To strengthen causal inference, colocalisation analysis and summary data based Mendelian randomisation were applied. Additional analyses included bulk RNA sequencing, single cell expression profiling, protein interaction mapping, and druggability assessment. These integrated approaches enabled a comprehensive evaluation of plasma protein biomarkers in urological cancer development.
Key Protein Targets and Risk Associations
In bladder cancer, four protein markers were identified. PSCA was associated with increased risk, while GSTM1, GSTM3, and GSTM4 were linked to decreased risk. These proteins were primarily expressed in pericytes, urothelial cells, and natural killer cells within tumour tissue.
In prostate cancer, 15 protein markers were identified, with seven associated with increased risk: AGER, ALAD, CHMP2B, PEX14, ZG16B, PPP1R14A, and SERPINA3. Eight proteins were linked to reduced risk: BTN2A1, CEACAM21, DNAJB9, MSMB, PYGL, HLA-E, SOD2, and TOR1AIP1. These markers were enriched in epithelial cells and monocytes or macrophages in prostate tumours.
The strongest evidence from Mendelian randomisation and colocalisation analyses supported GSTM4 in bladder cancer and SOD2 and CHMP2B in prostate cancer as causal biomarkers.
Clinical Implications and Therapeutic Potential
Notably, seven of the identified plasma protein biomarkers have previously been targeted by drugs developed for other malignancies and immune related conditions, suggesting potential for therapeutic repurposing in urological cancer. These findings highlight the dual role of plasma proteins as both predictive biomarkers and candidate drug targets.
The study provides robust evidence supporting the clinical relevance of plasma protein biomarkers in urological cancer risk stratification and treatment development. With regard to translation into practice, these insights may guide future biomarker driven strategies and accelerate drug discovery efforts in this diverse group of malignancies.
Reference
Lyu X et al. Identification of novel protein markers and therapeutic targets for common urological cancers by integrating large-scale human plasma proteome with the genome. Sci Rep. 2026; doi: 10.1038/s41598-026-49333-1.
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