DNA Repair Pathway Alterations in Bladder Cancer

Urothelial cells are under constant exposure to endogenous and exogenous sources of DNA damage. Multiple DNA repair pathways are active in normal urothelial cells and coordinate to repair damage and maintain genomic integrity. However, loss of DNA repair fidelity is common in tumors, and DNA repair genes are among the most frequently mutated genes in bladder cancer. Multiple lines of preclinical and clinical evidence indicate that bladder tumor DNA repair pathway deficiency drives unique biological properties and therapeutic vulnerabilities. This chapter reviews the major sources of DNA damage in urothelial cells and the genomic consequences of mutagen exposure. In addition, we discuss the frequency and biological impact of alterations in critical DNA repair pathways including mismatch repair (MMR), homologous recombination (HR) repair, and nucleotide excision repair (NER). Finally, we highlight several recent and on-going bladder cancer clinical trials designed to test the impact of targeting specific DNA repair-deficient states. DNA repair deficiency is a defining feature of a subset of bladder tumors and efforts to therapeutically exploit DNA repair deficiency hold promise in several bladder cancer clinical settings.