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

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Upper tract urothelial carcinoma (UTUC) represents a significant proportion of urothelial malignancies in China, with limited molecular understanding impacting diagnosis and treatment.
• The higher incidence in China compared to Western countries necessitates further investigation into UTUC's molecular underpinnings.

Purpose of the Study:

• To explore molecular mechanisms driving UTUC.
• To identify potential diagnostic and therapeutic biomarkers for UTUC through integrative multi-omics analysis.
• To enhance understanding of UTUC's molecular landscape for improved patient outcomes.

Main Methods:

• Analysis of 48 paired UTUC tumor and adjacent normal tissues using RNA and whole-exome sequencing.
• Weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes associated with pathological traits.
• Validation through survival analysis, cross-cancer evaluation (TCGA-BLCA), independent cohort confirmation, and immunohistochemistry (IHC).

Main Results:

• Identification of 3968 differentially expressed genes involved in genitourinary development and calcium signaling.
• WGCNA highlighted four co-expression modules linked to infiltration, with 64 genes associated with pathological traits.
• Methionine sulfoxide reductase B3 (MSRB3) and Synaptopodin 2 (SYNPO2) were prioritized as hub genes, showing trends toward poorer survival and reduced protein expression in UTUC.

Conclusions:

• Integrative multi-omics analysis suggests MSRB3 and SYNPO2 as candidate biomarkers for UTUC progression.
• These findings provide valuable insights for risk stratification strategies in UTUC.
• The study supports the potential for MSRB3 and SYNPO2 in the development of novel therapeutic approaches for UTUC.