Survival of patients with urothelial
carcinoma (including
bladder cancer and upper tract urothelial
carcinoma) is limited by our current approaches to staging, surgery, and
chemotherapy. Large-scale, next-generation sequencing collaborations, such as The
Cancer Genome Atlas, have already identified drivers and vulnerabilities of urothelial
carcinoma. This disease has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours, potentially resulting in an increased neoantigen burden. Mutational heterogeneity is mediated by multiple factors including the
apolipoprotein B mRNA editing enzyme catalytic
polypeptide family of
enzymes, smoking exposure, viral integrations, and intragene and intergene fusion
proteins. The mutational landscape of urothelial
carcinoma, including specific mutations in pathways and driver genes, such as FGFR3, ERBB2, PIK3CA, TP53, and STAG2, affects tumour aggressiveness and response to
therapy. The next generation of
therapies for urothelial
carcinoma will be based on patient-specific targetable mutations found in individual tumours. This
personalized-medicine approach to urothelial
carcinoma has already resulted in unique clinical trial design and has the potential to improve patient outcomes and survival.