Chromothripsis

[1] The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time.

[4] The term chromothripsis is a neologism coined by scientists at the Wellcome Trust Sanger Institute[2] that comes from the Greek words χρῶμα, khrôma 'color' (representing chromosomes because they are strongly stained by particular dyes), and θρίψις, thrípsis 'shattering into pieces'.

Chromothripsis has been linked to the generation of oncogenic fusions in supratentorial ependymoma, chondromyxoid fibroma, and Ewing sarcoma, the latter two being bone tumours.

Using multiple molecular techniques of these germ line cells that have appeared to have undergone a chromothripsis like process, as well as inversions and translocations, duplications and triplications were also seen and hence increases in copy number.

[9] However most samples displaying chromothripsis that are analysed have low copy states and hence have paired end joining predominating repair mechanisms.

[3] One of the main characteristic features of chromothripsis is large numbers of complex rearrangements occurring in localised regions of single chromosomes.

[citation needed] Through genome sequencing of a Sonic hedgehog medulloblastoma (SHH-MB) brain tumour, a significant link between TP53 mutations and chromothripsis in SHH-MBs has been found.

It has also been shown that TP53 mutation-containing cells show a preference for low-fidelity repair mechanisms such as non-homologous end joining.

In order for micronuclei to progress through the cell cycle and induce chromosome damage, diminished levels of p53 have been seen to be needed.

[17][18] Defects in DNA damage response can cause increased frequency of micronucleus formation and hence the occurrence of chromothripsis.

[3] As well as cells encompassing DDR defects, they are likely to have repressed apoptotic mechanisms which will further enhance the occurrence of mutations and aneuploidy.

[1] Poor clinical outcomes in neuroblastomas (such as those caused by deletion of the FANC gene in Fanconi anaemia) have been linked to frequent chromothripsis occurrence.

[citation needed] It was pointed out that initial computational simulations underpinning the single-event nature of chromothripsis, which are central to the theory, did not necessarily prove the existence of a single event, and that known models of progressive cancer development do not contradict the occurrence of complex rearrangements.

[23] It has also been suggested that there is no single traumatic event, but that repeated breakage-fusion-bridge cycles might cause the complex genetic patterns.

[25] Additionally, research studies inducing telomere crises followed by sequencing the resultant clones demonstrated complex DNA rearrangements that directly recapitulated the one-off chromosomal catastrophe model of chromothripsis.