Chromothripsis

Chromothripsis is the phenomenon by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history. It is believed that for the cell to be able to withstand such a destructive event, the occurrence of such an event must be the upper limit of what a cell can tolerate and survive. The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time. Chromothripsis is the phenomenon by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history. It is believed that for the cell to be able to withstand such a destructive event, the occurrence of such an event must be the upper limit of what a cell can tolerate and survive. The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time. The simplest model as to how these rearrangements occur is through the simultaneous fragmentation of distinct chromosomal regions (breakpoints show a non-random distribution) and then subsequent imperfect reassembly by DNA repair pathways or aberrant DNA replication mechanisms. Chromothripsis occurs early in tumour development and leads to cellular transformation by loss of tumour suppressors and oncogene amplifications. In 2015, it was found that chromothripsis can also be curative: a woman who had WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, an extremely rare autosomal dominant combined immunodeficiency disease, found her symptoms disappeared during her 30s after chromothripsis of chromosome 2 deleted the disease allele. Chromothripsis is a neologism that comes from the Greek words chromo which means color (and represents chromosomes because they are strongly stained by particular dyes) and thripsis which means 'shattering into pieces'. Chromothripsis was first observed in sequencing the genome of a chronic lymphocytic leukaemia. Through paired end sequencing, 42 chromosomal rearrangements were found in the long arm of chromosome 4 and a significant number of rearrangements were found in regions of chromosomes 1, 12, and 15. Subsequent investigations using genome-wide paired-end sequencing and SNP array analysis have found similar patterns of chromothripsis in various human cancers, e.g., Melanomas, sarcomas and colorectal, lung and thyroid cancers. In subsequent investigations, about 25% of studied bone cancers displayed evidence of chromothripsis. Chromothripsis has been linked to the generation of oncogenic fusions in supratentorial ependymoma, chondromyxoid fibroma, and Ewing sarcoma, the latter two being bone tumours. Chromothripsis has been seen in 2–3% of cancers across all subtypes. The most widely accepted and straightforward model for chromothripsis is that within a single chromosome, distinct chromosomal regions become fragmented/shattered almost simultaneously and subsequently rejoined in an incorrect orientation. Deletion of certain fragments, including deletions that are a few hundred base pairs long, and hence gene segments is possible and consequently the production of double minute chromosomes. When multiple chromosomes are involved in chromothripsis, fragments of both chromosomes are joined together by paired end joining and the exchange of fragments between the original chromosomes. Rejoining of fragments require very minimal or even no sequence homology and consequently suggesting that nonhomologous or microhomologous repair mechanisms such as non-homologous end joining (NHEJ) and microhomology-mediated break induced repair (MMBIR) dominate double stranded break repair and are involved in modelling the chromothriptic landscape, opposed to homologous recombination which requires sequence homology. Joining of fragments and rearrangements have also been shown to take place on paternal chromosomes. As well as in cancer cells, chromothripsis has also be reported in patients with developmental and congenital defects, i.e. germ line cells. 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. This can be attributed to replicative processes that involve the restoration of collapsed replication forks such as fork stalling and template switching model (FoSTeS) or microhomology mediated break induced replication (MMBIR). This makes it seem that it would be more appropriate to name the phenomenon 'chromoanasynthesis' which means chromosome reconstitution rather than chromothripsis. However most samples displaying chromothripsis that are analysed have low copy states and hence have paired end joining predominating repair mechanisms. Further study of chromothripsis events and chromothriptic samples is required in order to understand the relative importance of paired end joining and replicative repair in chromothripsis. One of the main characteristic features of chromothripsis is that large numbers of complex rearrangements in localised regions of single chromosomes. The ability to cause such confined damage suggests that chromosomes need to be condensed e.g. in mitosis, for chromothripsis and chromosome rearrangements to be initiated.