DNA Amplification by Breakage/Fusion/Bridge Cycles Initiated by Spontaneous Telomere Loss in a Human Cancer Cell Line

Abstract

The development of genomic instability is an important step in generating the multiple genetic changes required for cancer. One consequence of genomic instability is the overexpression of oncogenes due to gene amplification. One mechanism for gene amplification is the breakage/fusion/bridge (B/F/B) cycle that involves the repeated fusion and breakage of chromosomes following the loss of a telomere. B/F/B cycles have been associated with low-copy gene amplification in human cancer cells, and have been proposed to be an initiating event in high-copy gene amplification. We have found that spontaneous telomere loss on a marker chromosome 16 in a human tumor cell line results in sister chromatid fusion and prolonged periods of chromosome instability. The high rate of anaphase bridges involving chromosome 16 demonstrates that this instability results from B/F/B cycles. The amplification of subtelomeric DNA on the marker chromosome provides conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are a mechanism for gene amplification in human cancer cells.

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…Metaphase chromosomes reflect events that occurred prior to the metaphase being examined and, with respect to some aberrations, researchers infer from studying the metaphase chromosomes that 'telomere dysfunctions' were likely. For example, unbalanced translocations, dicentric chromosomes, and terminally deleted chromosomes suggest a defect in telomeres that may involve capping defects, DNA damage affecting the telomeric ends, oncogene activation or other stimuli [Artandi et al, 2000;Gisselsson et al, 2001;Lo et al, 2002;Deng et al, 2003;Murnane and Sabatier, 2004;Louis et al, 2005].…”

Meiotic aberrations during 2n pollen formation in Begonia

“…'Florence Rita' and B276 formed a large number of chromosome bridges. Chromosome bridges have often been studied by irradiating and damaging chromosomes within the cell or pollen grain (Viccini and de Carvalho, 2002;Carballo et al, 2006), or by observing cancer cells containing chromosomes damaged by spontaneous telomere loss (Fouladi et al, 2000;Lo et al, 2002;Acilan et al, 2007). Damaged chromosomes enter the breakage-fusion-bridge cycle, which is well investigated in maize (Zheng et al, 1999).…”

Chromothripsis: Breakage-fusion-bridge over and over again

“…Differential transmission of chromosome segments in BFB, in multiple sequential events, thus causes heterogeneity and explains why individual markers appear in a non-integer CNum. Since amplification of small chromosome regions is a common consequence of ongoing BFB cycles, 24,25 BFB might also explain the sharp increase in the CNum of small regions, even exceeding ploidy of the corresponding chromosome arm (Fig. 3, arrows).…”

“…These indicate that two arms from different chromosomes are affected, and breakage along the chromosome arms can start BFB cycles in agreement with these examples. 24,25 In some cases, translocations accumulate in a sharply defined region along the chromosome arm. 1 Possibly, a fragile site 40 flanks such regions and provokes BFB in these cases of chromothripsis.…”