Dissecting Genetic Mechanisms of UTUC: A Network-Based Multi-Omics Cohort Study.

OBJECTIVE

Upper tract urothelial carcinoma (UTUC) accounts for about 31% of urothelial malignancies in China, a markedly higher proportion than in Western countries. Limited molecular understanding hampers diagnosis and therapy. This study aimed to explore molecular mechanisms and identify potential biomarkers through a cohort-based integrative multi-omics analysis.

METHODS

We analyzed 48 paired UTUC tumor and adjacent normal tissues. RNA and whole-exome sequencing were performed to explore difference. Weighted gene co-expression network analysis (WGCNA) was used to identify modules and hub genes associated with pathological traits. Validation included survival analysis within the discovery cohort, cross-cancer evaluation using The Cancer Genome Atlas Bladder Urothelial Carcinoma dataset (TCGA-BLCA) via gene expression profiling interactive analysis, and independent confirmation with a UTUC cohort from cBioPortal (n = 32). Protein expression was examined using immunohistochemistry (IHC) data from the Human Protein Atlas.

RESULTS

We identified 3968 differentially expressed genes enriched in genitourinary development and calcium signaling pathways. WGCNA revealed four co-expression modules associated with infiltration, with 64 genes linked to pathological traits. Integrative analysis prioritized methionine sulfoxide reductase B3 (MSRB3) and Synaptopodin 2 (SYNPO2) as hub genes. Within the UTUC cohort, both genes showed trends toward poorer progression-free survival; in TCGA-BLCA, their expression and survival patterns provided supportive cross-cancer evidence; and in the independent UTUC dataset, clinicopathological correlations were directionally consistent with the discovery findings. IHC suggested lower protein expression in UTUC compared with normal urothelium.

CONCLUSIONS

This integrative multi-omics cohort study suggests MSRB3 and SYNPO2 as candidate biomarkers for UTUC progression, offering insights for risk stratification and potential therapeutic development.