Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors

Previous molecular subtyping for bladder carcinoma (BLCA) involved 135 mo), an NMIBC subtype enriched in urothelial differentiation genes, shows a high frequency of actionable FGFR3 mutations, amplifications, and FGFR3-TACC3 fusion. Luminal-like (91.7 mo), predominantly NMIBC, has higher MAPK signaling and more KRAS and KMT2C/D mutations than other subtypes. Mesenchymal-like (MES; 86.6 mo) and Squamous-cell carcinoma-like (SCC; 20.6 mo) are predominant in MIBC. MES is high in AXL signaling, whereas SCC has elevated PD1, CTLA4 signaling, and macrophage M2 infiltration. About 20% of NMIBCs show MIBC subtype traits and a lower 5-yr OS rate than Papillary-like NMIBC (81% vs 96%). The main limitations of our study are the incomplete clinical annotation, and the analyses were based on transcriptome subset due to comparisons across gene expression quantification technologies. BLCA can be stratified into six molecular subtypes. NMIBC, with a high risk of progression, displays the molecular features of MIBC. Biomarkers are urgently needed to guide patient treatment selection and avoid unnecessary toxicities in those who fail to respond. We believe molecular subtyping is a promising way to tailor disease management for those who will benefit most. A gene expression analysis for over 2000 bladder carcinomas shows six potential clinically relevant molecular subtypes with distinct pathways and targetable vulnerability. Non–muscle-invasive bladder cancer with a high risk of progression displays molecular features of muscle-invasive disease.