Natural history of bladder cancer: Validation of the multiple pathway model in multi-omics era

First recognized about 2 hundred years ago, bladder cancer has continued to challenge both clinicians and researchers due to its inherent heterogeneity in frequent recurrence and progression. Forty-three years ago, Droller proposed a multiple pathway model to explain the disparate clinical behaviors of low-grade and high-grade bladder tumors. The model suggested genetic alterations that promote hyperplasia generate low-grade papillary tumors that recur but do not metastasize. Separate genetic alterations promote dysplasia, and dysplastic-hyperplastic tumor cells generate high-grade tumors that may invade and metastasize. Initial preclinical studies to the current multi-omics approaches show that while high-grade tumors arise from KRT5+ stem cells in the basal layer of the urothelium, low-grade tumors arise from the more differentiated intermediate cell layer. Mutations in genes on chromosome 9p (e.g., CDKN2A/p16INK4a), 9q (e.g., PTCH1, TSC1), STAG2, KDM6A, FGFR3, RAS and PI3KCA characterize low-grade papillary tumors, and a hyperproliferative phenotype. Conversely, mutations in TP53, MDM2, PTEN, and genomic instability are prevalent in high-grade tumors, especially muscle-invasive bladder cancer. The development of molecular classification systems, including molecular subtypes, have further affirmed the multiple pathway model. These developments underpin hopes for the development of personalized cancer treatment.