Molecular Pathogenesis: Field Cancerization and Clonal Evolution in Urothelial Cancer Initiation and Progression

Early histopathological studies performed on cystectomies from bladder cancer patients demonstrated that large areas of the urothelium display preneoplastic morphological changes. More recent whole-organ mapping studies revealed the presence of widespread genomic changes, including copy-neutral loss of heterozygosity and inactivating mutations in chromatin-modifying enzymes, even in areas that appear normal and in older individuals without cancer. Some of these mutations can be attributed to environmental exposures and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-mediated mutagenesis, but age-related mutagenic processes predominate in the normal areas and are associated with subclonal expansions that can occupy large areas of the urothelium. Cancer driver mutations and copy number variations then accumulate to produce high-grade dysplasia and carcinoma in situ (CIS) that serve as the immediate precursor lesions for invasive urothelial cancer. The available evidence suggests that basal or luminal molecular subtype commitment occurs very early in bladders with unifocal cancers whereas molecular subtypes can be mixed in bladders with multifocal cancers. More is known about cancer initiation than progression, which is associated with transient inflammation in luminal and chronic inflammation in basal preclinical models. These observations have important implications for cancer prevention and the detection and clinical management of patients with bladder cancer.