Clinical and molecular characteristics of bladder urothelial carcinoma subtypes

Bladder urothelial carcinoma (BLCA) is a common malignancy with high heterogeneity. A reasonable molecular subtyping can facilitate biological study and personalized therapy of BLCA. In this study, unsupervised consensus clustering was used to acquire the molecular subtypes of BLCA based on messenger RNA (mRNA) and microRNA (miRNA) data. Gene signature markers and canonical signaling pathways were compared between different subtypes. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for the functional annotation of overexpressed genes in different subtypes for Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Three molecular subtypes were identified including C1 (luminal-P53 like), C2 (luminal-other), and C3 (basal-immune-squamous). C2 was different from C1 and C3 in clinical characteristics, including younger, better prognosis, and a higher proportion of papillary, Asian, low-grade, early-stage, lymph node negative, and complete remission patients (P < 0.05). Three molecular subtypes also showed distinct mRNA and miRNA expression patterns. luminal and P53-like markers were highly expressed in subtype C1, luminal markers were highly expressed in subtype C2, and basal, EMT/claudin-low, immune and squamous-differentiation markers were highly expressed in subtype C3. In addition, highly expressed genes in C1 were involved in extracellular signal transduction and cell-cell interaction, highly expressed genes in C2 were associated with oxygen transport, energy and steroid metabolism, and highly expressed genes in C3 were related with inflammatory, immune, cytokine, and signal transduction. BLCA in different molecular subtypes showed different clinical and molecular characteristics and personalized therapy needed to be adopted according to the molecular subtypes.