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Dissecting Genetic Mechanisms of UTUC: A Network-Based Multi-Omics Cohort Study
Tingting Fu1,2, Banghua Liao3, Yong Yang3
1Department of Urology, Lab of Health Data Science, Innovation Institute for Integration of Medicine and Engineering, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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.
