摘要：SummaryWhole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multipleHOXgenes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of mucosa. The α mutations occurred at low frequencies while the β mutations increased in frequency with disease progression. Modeling revealed that bladder carcinogenesis spans 10–15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was driven by β mutations.Graphical abstractDisplay OmittedHighlights•Dysregulation of multiple ILs plays a role in bladder cancer initiation•Altered HOX genes and oncogenic pathways complement dysregulated immunity•Bladder carcinogenesis comprises dormant and progressive phases•The dormant and progressive phases are driven by α and β mutations respectivelyMolecular biology; Cell biology; Cancer
