Could chromosomal catastrophes cause cancer?
Scientists have uncovered evidences that our cells can undergo hundreds of mutations in a single chromosomal catastrophe that can trigger the rapid development of cancer. The findings, published in the journal Cell, contradict the idea that cancer development is always a slow affair, with harmful mutations accumulating gradually over time. The scientists, from the UK and the US, have named the newly described phenomenon 'chromothripsis', from the Greek terms chromos ('chromosome') and thripsis ('shattering into pieces'). In fact, the majority of cancers develop slowly, and it may take years or even decades before a tumour builds up enough mutations to progress from the pre-cancerous phase to the malignant stage. However, sometimes cancers seem to appear from nowhere. In this study, researchers analysed the genomes of a number of cancer samples. The majority of samples apparently followed the conventional path of cancer development, with mutations building up gradually. In a small number of samples, however, a single cataclysmic event appears to have taken place that caused tens or even hundreds of mutations in one fell swoop. 'The results astounded us,' commented the lead author of the paper, Dr Peter Campbell of the Wellcome Trust Sanger Institute in the UK. 'It seems that in a single cell in a single event, one or more chromosomes basically explode - literally into hundreds of fragments.' Usually, cells would not survive a disaster of this nature. However, sometimes the cell's DNA (deoxyribonucleic acid) machinery attempts to repair the damage. 'The cell should say, "That's it," and give up, but instead it tries to piece the chromosomes back together like a valuable piece of porcelain,' explained Dr Campbell. The results of this attempted repair job are often disastrous, as the resulting genome is riddled with large numbers of mutations that may accelerate the cell along the path towards cancer development. The researchers found that one colorectal cancer sample had 239 rearrangements on one single chromosome. According to the scientists, around 2-3% of all cancer genomes bear the hallmarks of chromothripsis. The phenomenon appears to be particularly common in bone cancers, with 25% of cases affected. In one bone cancer sample, three cancer genes were mutated in a single event. The pattern of damage suggests that chromothripsis occurs during cell division, when the chromosomes are much more compact than usual. As to the causes, the number one suspect is ionising radiation. 'Well-known to induce dsDNA [double-stranded DNA] breaks, a pulse of ionising radiation could cut a swathe through a condensed chromosome and [...] generate breaks involving a band, an arm or the whole chromosome,' the researchers write. The team now plans to study the cancers of people with a known history of exposure to ionising radiation to see if they have undergone chromothripsis. 'If we can understand its roots, then we may learn how to prevent that kind of damage from happening,' Dr Campbell noted. Another possibility is that the damage arises during the process of telomere attrition, the natural shortening of the tips of the chromosomes. As the researchers point out, most of the chromothripsis damage observed in the study involved chromosome regions extending to the telomeres. 'Whatever the mechanism of damage, the consequences are profound,' the researchers conclude. 'Faced with hundreds of DNA breaks, the cell's DNA repair machinery attempts to rescue the genome. The resultant hodgepodge bears little resemblance to its original structure, and the genomic disruption has wholesale and potentially oncogenic effects.'For more information, please visit: Wellcome Trust Sanger Institute:http://www.sanger.ac.uk Cell:http://www.cell.com
Countries
United Kingdom, United States