Box 1 | Defining chromothripsis

From the following article:

Chromothripsis and cancer: causes and consequences of chromosome shattering

Josep V. Forment, Abderrahmane Kaidi & Stephen P. Jackson

Nature Reviews Cancer 12, 663-670 (October 2012)

doi:10.1038/nrc3352

Chromothripsis, which literally means 'chromosome shattering', is a phenomenon that has recently been reported to occur in cells harbouring complex genomic rearrangements (CGRs). Chromothripsis was initially inferred from studies of cancer cells, based on the combined use of next-generation DNA sequencing and bioinformatics analyses, and was defined on the basis of three main features: the occurrence of remarkable numbers of rearrangements in localized chromosomal regions; a low number of copy number states (generally between one or two) across the rearranged region; and alternation in the chromothriptic areas of regions where heterozygosity is preserved with regions presenting loss of heterozygosity (LOH). Although these are considered to be the defining features of chromothripsis, further delimitation of these characteristics may help in future detection and definition of chromothriptic events, and may help to answer some remaining questions. For example, one area of uncertainty is the precise number of breakpoints that defines chromothripsis. The initial reports showed that the number of breakpoints in samples defined as chromothriptic ranged from tens to hundreds. Such variation, therefore, suggests that the number of breakpoints per se may not be the defining factor of chromothripsis but rather that the mechanisms driving chromothripsis tend to result in many rearrangements. However, there might be a requirement for a minimum number of breaks to allow the complex rearrangements observed during chromothripsis. Related to this, although most examples of chromothripsis reported in the literature display intrachromosomal events, some show the involvement of a few chromosomes (up to four in some cases3). When considering micronuclei as a spatial platform for chromothripsis, only one or two chromosomal regions might be involved. However, it is possible that consecutive chromothriptic events may take place in a time frame that does not subsequently allow them to be distinguished as having taken place separately (that is, within a time frame in which variation of copy number states or LOH did not have the opportunity to occur).

Another issue is whether the maintenance of a low number of copy number states is truly a defining characteristic of chromothripsis, or whether it is more of a reflection of chromothripsis generally arising by repairing shattered chromosomes by end-joining mechanisms. In this regard, it is important to consider that, in some chromothriptic events described in cancer cells17, and in other CGRs with characteristics of chromothripsis identified in patients suffering genomic disorders19, the number of copy number states actually varies substantially owing to the appearance of amplifications at the chromosomal breakpoints. Consequently, chromothripsis generated through chromosome shattering and end-joining-mediated repair will invariably lead to the maintenance of a low number of copy number states, and chromothripsis generated through aberrant replication-based mechanisms could result in regions with a more diverse number of copy number states. Although most analyses favour chromothripsis in cancer cells occurring through end-joining-mediated repair3, 14, 17, 18, we feel that replication-based alternatives should also be considered as chromothriptic events if they fulfil the other chromothriptic criteria listed above.