The Genomic Characteristics and Origin of Chromothripsis

Abstract

In 2011 a phenomenon involving complex chromosomal rearrangements was discovered in cancer genomes. This phenomenon has been termed chromothripsis, on the basis of its chromosomal hallmarks, which point to an underlying process involving chromosome (chromo) shattering (thripsis). The prevailing hypothesis of cancer genome evolution as a gradual process of mutation and selection was challenged by the discovery of chromothripsis, because its patterns of chromosome rearrangement rather indicated an one-off catastrophic burst of genome rearrangement. The initial discovery of chromothripsis has led to many more examples of chromothripsis both in cancer genomes as well as in patients with congenital diseases and in the genomes of healthy individuals. Since then, a burning topic has been the study of the molecular mechanism that leads to chromothripsis. Cumulating evidence has shown that chromothripsis may result from lagging chromosomes encapsulated in micronuclei, as well as from telomere fusions followed by chromosome bridge formation. In this chapter, we will outline the genomic characteristics of chromothripsis, and we present genomic methodologies that enable the detection of chromothripsis. Furthermore, we will give an overview of recent insights into the mechanisms underlying chromothripsis.

Established and Novel Mechanisms Leading to de novo Genomic Rearrangements in the Human Germline

“…Chromothripsis results in massive chromosomal reconstruction with or without deletion. The breakpoints are usually consistent with canonical NHEJ [Kloosterman et al, 2011;Stephens et al, 2011;Marcozzi et al, 2018;Zepeda-Mendoza and Morton, 2019]. In addition, the pulverized DNA fragments may also be reassembled via alternative end-joining or via the co-occurrence of NHEJ and alternative end-joining [Kloosterman et al, 2012;Slamova et al, 2018].…”

“…To date, constitutional rearrangements indicative of chromothripsis have been identified in multiple individuals [Kloosterman et al, 2011[Kloosterman et al, , 2012de Pagter et al, 2015;Fukami et al, 2017;Marcozzi et al, 2018]. Most of these individuals exhibited severe developmental delay and congenital malformations, which are ascribable to abnormal expression of genes on the affected chromosomes.…”

“…Chromoanasynthesis is characterized by microhomologies around breakpoints. Unlike chromothripsis, chromoanasynthesis is frequently associated with amplifications [Liu et al, 2011a;Marcozzi et al, 2018;Nazaryan-Petersen et al, 2018;Zepeda-Mendoza and Morton, 2019]. Chromoanasynthesis can create multiple CNVs clustered on a single chromosome [Liu et al, 2011a;.…”

“…Chromoplexy is different from chromothripsis in the following ways: (1) it involves multiple chromosomes, (2) it creates fewer breakpoints in 1 chromosome than those created by chromothripsis, and (3) it is implicated primarily in the translocations of somatic cells [Berger et al, 2011;Baca et al, 2013;Marcozzi et al, 2018;Zepeda-Mendoza and Morton, 2019]. However, chromoplexy has several similar characteristics to chromothripsis, such as copynumber-neutral rearrangements with NHEJ-compatible breakpoint structures.…”

De Novo Small Supernumerary Marker Chromosomes Arising From Partial Trisomy Rescue

“…Trisomy rescue is assumed to occur in micronucleus, an aberrant cellular component frequently observed in cancer cells and, to a lesser extent, in normal cells (Zhang et al, 2015;Marcozzi et al, 2018). A micronucleus encapsulates one or a few chromosomes to separate them from the other chromosomes in the main nucleus ( Figure 1A) (Zhang et al, 2015).…”