Contemporary Molecular Classification of Urinary Bladder Cancer

Abstract

The significant heterogeneity in the clinical outcome among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive and non-muscle-invasive bladder cancer. Transcriptional profiling studies revealed that primary bladder cancers can be grouped into ‘intrinsic’ basal and luminal molecular subtypes. Luminal tumors have a papillary configuration and express markers of urothelial differentiation (uroplakins, cytokeratin 20) fibroblast growth factor 3 (FGFR3), E-cadherin and early cell-cycle genes. On the contrary, basal tumors express markers of the basal layer of the urothelium (cluster of differentiation 44, cytokeratin 5/6 and cytokeratin 14); some show squamous differentiation. Patients with basal tumors respond better to immune checkpoint inhibitors and have a worse prognosis than those with luminal tumors, who respond better to FGFR3 and human epidermal growth factor receptor 2. Patients with squamous differentiation tumors show better response to agents targeting epidermal growth factor receptor. The aim of this review was to highlight the chronological order of research performed in the field of the molecular classification of bladder cancer, with particular emphasis on prototypical research projects and recent advances. If prospective studies confirm the association of bladder cancer molecular subtypes with different responses and prognoses to targeted therapies, molecular subtyping will be incorporated into bladder cancer management.