Chromosome instability in neoplasia: chaotic roots to continuous growth.
Multiple rearrangements of chromosome number and structure are common manifestations of genomic instability encountered in mammalian tumors. In neoplasia, in continuous immortalized growth in vitro, and in animal models, the accumulation of various defects on DNA repair and telomere maintenance machineries, mitotic spindle abnormalities, and breakage-fusion-bridge cycles, deteriorate the precise mitotic distribution of the genomic content, thus producing various types of chromosomal anomalies. These lesions generate tremendous genomic imbalances, which are evolutionary selected, since they force the function of the whole genome towards continuous growth. For more than a century chromosomal rearrangements and aneuploidy in neoplasia have been discussed and a vast number of genes and pathways, directly or indirectly implicated, have been described. In this review, we focus on the biological mechanisms that generate numerical or structural deviations of the normal diploid chromosomal constitution in epithelial neoplasia. There is growing evidence that chromosomal instability is both an epiphenomenon and a leading cause of cancer. We will discuss the roles of genes, chromosome structure, and telomere dysfunction in the initiation of chromosomal instability. We will explore research strategies that can be applied to identify rates of chromosomal instability in a specimen, and the putative biological consequences of karyotypic heterogeneity. Finally, we will re-examine the longstanding hypothesis of the generation of aneuploidy in the context of telomere dysfunction and restoration.
Gagos
Sarantis
S
Laboratory of Genetics, Foundation for Biomedical Research of the Academy of Athens Greece, Soranou Efessiou 4, Athens 11527, Greece. sgagos@bioacademy.gr
Irminger-Finger
Irmgard
I
D000782:Aneuploidy; D043171:Chromosomal Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D016615:Telomere / Q000502:physiology*