From Normalcy to Neoplasia: Mutational Events During Bladder Tumor Evolution

Wind back the tape of life, and let it play again. Would the replay ever yield anything like the history that we know—Stephen Jay Gould in a Wonderful Life. The genetic steps resulting in cancer are an evolutionary process that follows Darwinian evolution and natural selection. Normal cells in the human body have limited replicative potential and, in a stepwise fashion, evolve progressively to a neoplastic state that precedes a tumor. Each step allows the cell to gain “hallmark” capabilities, including but not limited to cellular proliferation and immune evasion. During the evolution of a tumor, a shift from “normal” is observed at all scales, from the tiniest of post-translational modifications that can alter how the genome of a tumor cell is packaged in the nucleus, to changes in regulatory networks and metabolic demands. At the molecular level are the mutational events that are unique not just to each patient but also to each tissue type (Haigis et al., Science 363:1150–1151, 2019). Large-scale chromosomal deletions, translocations, and events such as chromothripsis are at the chromosomal scale. Through transient epigenetic changes or more permanent genetic changes, tumor cells transform the environment within the organ of origin into one suitable for unrestricted growth. By tracing the clonal evolutionary map of mutations, it is possible to understand the needs of a developing tumor, track the events that lead to the genesis of bladder cancer from normal bladder epithelium (urothelium), and understand how these changes help shape the bladder microenvironment into a more hospitable home for the tumor. In this chapter, we explore the ongoing research into mutational events identified in bladder cancer at different disease stages and the role these mutations play in helping the tumor survive and flourish.