The role of genetic instability in the pathogenesis and progression of urothelial carcinoma

Cancer appears to arise as a series of rate limiting steps, each of which represents the attainment of one cellular capability necessary for uncontrolled growth and invasion. As alterations in gene number or sequence can lead to the development of these cellular capabilities, the regulation of DNA fidelity is a vital homeostatic process. Mechanisms that disrupt DNA regulation lead to genomic instability and occur on two levels affecting either chromosomes (CIN; chromosomal instability) or individual DNA nucleotides (MSI; microsatellite instability). We conducted a search of the current literature to evaluate the evidence for the genomic instability in urothelial carcinoma (UC), and discuss the clinical role of the molecular pathways. Whilst CIN occurs more frequently in UC than MSI, the MSI molecular pathway is better understood. Distinct patterns of MSI occur in upper and lower urinary tract UC and produce tumours with a distinctive phenotype. Investigations into the mechanism of MSI in UC have revealed insights into the global pathogenesis of UC, similarities with other anatomically distant cancers and novel therapeutic strategies. The molecular mechanisms of CIN remain elusive. © 2005 Elsevier B.V. All rights reserved.