Integration of genetic, proteomic, and transcriptomic data identifies therapeutic targets and prognostic biomarkers...

Bladder cancer (BC) is a prevalent urinary tract malignancy with high morbidity and mortality. Despite advances in therapeutic modalities, early diagnosis and precise treatment remain challenging, highlighting the need for reliable biomarkers and therapeutic targets. This study aims to identify molecular targets and drug candidates for BC by integrating cross-omics quantitative trait loci (xQTLs), OLINK proteomics (a high-throughput plasma protein measurement platform), and transcriptomics data, alongside prospective cohort studies and multi-omics analyses.

We utilized data from the UK Biobank Pharma Proteomics Project (UKB-PPP), deCODE Genetics, and the Atherosclerosis Risk in Communities study (ARIC). Protein quantitative trait loci (pQTLs) associated with BC were screened via Summary-data-based Mendelian Randomization (SMR). Associations between proteins and BC risk were evaluated using Cox regression and a random survival forest (RSF) model. Drug targets were identified through genome-wide association studies (GWAS) and co-localization, while expression quantitative trait loci (eQTLs) analyses and single-cell RNA sequencing investigated gene expression and cellular heterogeneity. Methylation quantitative trait loci (mQTLs) analysis provided insights into epigenetic mechanisms.

Among the 16 proteins associated with BC, seven exhibited a positive correlation: MFGE8, ROR1, CTSS, CLEC4G, PLAT, CD59, TNFRSF19. The RSF model demonstrated superior performance. Co-localization analyses identified WFDC1, GSTM4, and RHOC as potential drug targets. Molecular docking validated camptothecin and lycorine as promising therapeutic candidates. eQTLs analyses implicated MFGE8, CTSS, TNFRSF19, and IL1RAP in BC risk and prognosis. Methylation analyses indicated complex regulation of CTSS and TNFRSF19.

WFDC1, RHOC, and GSTM4 exhibit therapeutic potential, while MFGE8, CTSS, TNFRSF19, and IL1RAP predict risk and prognosis, providing insights for precision diagnosis and treatment.