Comprehensive molecular characterization of urothelial bladder carcinoma

TLDR

Urothelial carcinoma of the bladder is a common malignancy causing approximately 150,000 deaths per year worldwide, and no molecularly targeted agents have been approved for its treatment. This study aims to provide a comprehensive molecular landscape of urothelial carcinoma by integrating genomic, transcriptomic, and proteomic data from 131 tumors as part of The Cancer Genome Atlas project. The authors performed whole‑genome, RNA, and microRNA sequencing, along with protein profiling, to identify recurrent mutations, fusions, and expression subtypes across the tumor cohort. They discovered recurrent mutations in 32 genes, including novel cancer genes, identified four expression subtypes, detected FGFR3‑TACC3 fusions and viral integrations, and found actionable targets in 69 % of tumors, notably PI3K/AKT/mTOR and RTK/MAPK pathways, with chromatin regulator mutations being the most frequent.

Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.