Tumor heterogeneity in muscle-invasive bladder cancer

Muscle-invasive bladder cancer (MIBC), a highly heterogeneous disease, shows genomic instability and a high mutation rate. Clinical outcomes are variable and responses to conventional chemotherapy differ among patients (due to inter-patient tumor heterogeneity and inter-tumor heterogeneity) and even within each individual tumor (intra-tumor heterogeneity). Emerging evidence indicates that tumor heterogeneity may play an important role in cancer progression, resistance to therapy, and metastasis. Comprehensive molecular subtyping classifies MIBC into distinct categories that have potential to guide prognosis, patient stratification, and treatment. Genomic characterization of time-series analyses at the single cell level, and of cell-free circulating tumor DNA or circulating tumor cells, are emerging technologies that enable dissection of the complex clonal architecture of MIBC. This review provides insight into the clinical significance of the molecular mechanisms underlying heterogeneity, focusing on inter- and intra-tumor heterogeneity, with special emphasis on molecular classification and methods used to analyze the complex patterns involved.