Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma

Area of Science:

• Oncology
• Genomics
• Urology

Background:

• Upper urinary tract urothelial cancer (UTUC) presents distinct etiologic and genomic factors compared to bladder cancer.
• Understanding UTUC's unique genetic landscape is crucial for targeted therapies.

Purpose of the Study:

• To comprehensively characterize the genomic landscape of UTUC.
• To identify distinct molecular subtypes and their clinical implications.

Main Methods:

• Whole-exome sequencing (WES) of DNA and RNA sequencing (RNAseq) on 31 UTUC samples.
• Integrated genomic analyses including DNA mutations, gene expression, and protein analysis.
• Unsupervised consensus hierarchical clustering (UCHC) to identify molecular subtypes.

Main Results:

• Identified frequent mutations in FGFR3 (74.1%), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%).
• Discovered four molecular subtypes based on RNAseq data, each with distinct clinical features and mutation patterns.
• Identified a novel SH3KBP1-CNTNAP5 fusion potentially regulating RTK signaling.

Conclusions:

• UTUC exhibits unique mutation frequencies and four distinct molecular subtypes compared to bladder cancer.
• The identified subtypes possess unique clinical behaviors and may respond differently to therapies.
• Further research is needed to validate subtypes and explore therapeutic strategies for the novel fusion mutation.