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Chromothripsis and cancer: causes and consequences of chromosome shattering
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Chromothripsis and cancer: causes and consequences of chromosome shattering
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Journal Article
Chromothripsis and cancer: causes and consequences of chromosome shattering
2012
Overview
Key Points
Chromothripsis is a phenomenon by which tens to thousands of chromosomal rearrangements occur, with the available evidence indicating that chromothripsis can be generated by a single catastrophic event during the life history of a cell.
Rearrangements can occur by chromosome shattering and rejoining of pieces by end-joining DNA repair pathways, or by aberrant DNA replication-based mechanisms.
Chromothripsis may contribute to cellular transformation, as it occurs early in tumour development: end-joining-based repair can lead to the loss of tumour suppressor functions, oncogenic fusions and oncogene amplification via double-minute chromosomes. In addition, aberrant DNA replication mechanisms taking place during chromothripsis can lead to oncogene amplification.
An attractive model for the generation of chromothripsis invokes the involvement of micronuclei. According to this model, chromosomes contained within micronuclei suffer aberrant DNA replication and can then be pulverized in mitosis with subsequent rejoining of DNA segments leading to a derivative chromosome or chromosomes that can be reincorporated into the main nucleus. Chromothripsis is observed with a higher frequency in cells with mutated p53. This leads to a model in which micronuclei formation owing to chromosome segregation errors is allowed in p53-deficient cells, potentially yielding chromothripsis and the evolution of cancer. Defects in chromosome segregation and/or DNA damage response processes may also contribute to carcinogenesis by promoting chromothripsis.
Chromothripsis is an emerging phenomenon that results in chromosome rearrangements in tumour cells. This Review discusses the possible mechanisms underlying this process and its implications for cancer biology and in the clinic.
Genomic alterations that lead to oncogene activation and tumour suppressor loss are important driving forces for cancer development. Although these changes can accumulate progressively during cancer evolution, recent studies have revealed that many cancer cells harbour chromosomes bearing tens to hundreds of clustered genome rearrangements. In this Review, we describe how this striking phenomenon, termed chromothripsis, is likely to arise through chromosome breakage and inaccurate reassembly. We also discuss the potential diagnostic, prognostic and therapeutic implications of chromothripsis in cancer.
