Chromosome instability

Abstract

Two levels of genetic instability have recently been characterized in human cancers: Subtle sequence changes observed at the nucleotide level and instability that is visible at the chromosomal level (Lengauer et al., Nature 396(6712):643-649, 1998). The high incidence of chromosome instability reported in neoplastic processes has made this an area of active investigation. Chromosome instability describes a variety of chromosome alterations, including numerical and structural chromosomal rearrangements observed at an increased rate when compared with normal controls. Numerical changes can be the consequence of abnormal segregation at the metaphase/anaphase transition. Dysregulation of genes involved in chromosome condensation, sister chromatid cohesion, kinetochore structure and function, and centrosome/microtubule formation and dynamics have been implicated in the formation of aneuploidy, hypodiploidy, and polyploidy, as have cell cycle checkpoint genes. Chromosome breaks and telomere dysfunction can result in various structural rearrangements (deletions, duplications, inversions, insertions, and translocations). Impairment of DNA repair, DNA replication, or DNA recombination is responsible for causing sister chromatid exchanges, fragile sites, chromatid/chromosome breaks, and mutagen sensitivity.