Chromothripsis: Chromosomes in Crisis

Abstract

Summary During oncogenesis, cells acquire multiple genetic alterations that confer essential tumor-specific traits, including immortalization, escape from anti-mitogenic signaling, neovascularization, invasiveness, and metastatic potential. In most instances, these alterations are thought to arise incrementally over years if not decades. However, recent progress in sequencing cancer genomes has begun to challenge this paradigm, as a radically different phenomenon, termed chromothripsis, has been suggested to cause complex intra- and inter-chromosomal rearrangements on short timescales. In this article, we review established pathways crucial for genome integrity and discuss how their dysfunction could precipitate widespread chromosome breakage and rearrangement in the course of malignancy.

ATRX contributes to epigenetic asymmetry and silencing of major satellite transcripts in the maternal genome of the mouse embryo

“…A high frequency of human pancreatic neuroendocrine tumors and pediatric glioblastomas exhibit loss of ATRX function (Elsasser et al, 2011;Jiao et al, 2011;Molenaar et al, 2012) and mutations in the human ATRX gene have been recently detected in aggressive high-stage neuroblastomas that exhibit complex chromosomal rearrangements and chromothripsis, an extreme form of chromosome shattering (Jones and Jallepalli, 2012;Molenaar et al, 2012). However, the molecular mechanisms of ATRX function and its role in maintenance of chromosome stability are not known at present.…”

Genome chaos: Survival strategy during crisis

“…10 Excitement surrounding these phenomena has generated many hypotheses about their mechanisms. 9,[11][12][13][14][15][16][17] Unfortunately, up to now, genome chaos studies have only monitored the end products of evolution in resected tumors and attempted to infer the evolutionary process from the sequencing data without monitoring the entire evolutionary process. In addition, current sequencingbased studies homogenize heterogeneous populations of cells, reducing the amount of genome chaos that is detected, underestimating its true frequency.…”

Lechromothripsis

“…Ainsi, la fragmentation de la chromatine déclenchée par l'apoptose pourrait être interrompue, voire inversée, comme cela a été démontré récemment [22], ce qui permet à la cellule de réparer tant bien que mal les cassures de son ADN et de survivre (Figure 2). Jones et Jallepalli [23] ont aussi suggéré que l'apparition du chromothripsis puisse résulter de l'effet combiné des erreurs mitotiques de ségrégation, de l'instabilité chromosomique générée et du stress réplicatif qui en découle. Ce stress peut créer des points de cassure au niveau des origines de réplication [24].…”