Common Chromosomal Fragile Sites and Cancer

Abstract

Chromosomal fragile sites are specific loci that show gaps, breaks, or rearrangements in metaphase chromosomes when cells are cultured under conditions that partially inhibit DNA synthesis, inducing replication stress. The common fragile sites (CFS) are numerous in the human genome, and are essentially observed in all individuals. Although the molecular basis for chromosome fragility of CFSs remains incompletely understood, there is now general agreement that CFS sequences have a distinct replication programme that combines late replication with failure to activate origins in the core regions of the CFSs during replication stress, resulting in the failure to complete replication. The CFSs exhibit several features characteristic of highly unstable or recombinogenic regions of the genome, and CFSs have been shown to mediate genetic instability in cancers, including during the early stages of tumourigenesis. In this chapter, we review the molecular features of CFSs, as well as the relationship of CFSs to genomic alterations in cancer cells.