Fragilome: Determining the role of fragile sites in human disease

Abstract

Genetic instability is a hallmark of at least the majority of cancer cells. While the normal cell has evolved specific molecular mechanisms involving both repair pathways to ensure DNA replication fidelity and checkpoints to maintain chromosomal stability during cellular multiplication, the cancer cell often to large extent has lost the ability to maintain genomic integrity. The consequence is often widespread genomic instability, which in most advanced cancers can be demonstrated as chromosomal rearrangements, such as deletion, translocation and amplification. Independent genomic damage at different genetic loci among members of tumour cells in the same affected patient will result in the generation of genetic tumour cell heterogeneity. One of the molecular pathways for chromosomal rearrangements starts from ‘fragile sites’. These are non-random predetermined chromosomal breakage regions of the genome that can be activated experimentally by a number of exogenous challenges. In the recent years, there has been exciting progress in this field, and molecular pathways have been described that identify the activation of fragile sites