The cancer biology of whole-chromosome instability

Duijf, Pascal H.G.; Benezra, Robert

doi:10.1038/onc.2012.616

Cited by 114 publications

(112 citation statements)

References 155 publications

(205 reference statements)

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“…This feature was recognized early on in human tumors (see Boveri 2008, for an English translation), but its importance has been obscured by the complexity of the cancer phenotype. Multiple mechanisms have been described to account for the high rate of whole-chromosome segregation errors (wCIN) and structural aberrations (sCIN) in cancerand have been comprehensively discussed elsewhere (Lengauer et al 1998;Ganem et al 2007;Holland and Cleveland 2009;Burrell et al 2013b;Duijf and Benezra 2013). Here, we will briefly summarize some of the key defects leading to CIN, emphasize the importance of phenotypes allowing the expansion of highly aneuploid cells, and discuss its impact on tumor progression and treatment.…”

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confidence: 99%

The Role of Aneuploidy in Cancer Evolution

Sansregret

Swanton

2016

Cold Spring Harb Perspect Med

215

163

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Chromosomal aberrations during cell division represent one of the first recognized features of human cancer cells, and modern detection methods have revealed the pervasiveness of aneuploidy in cancer. The ongoing karyotypic changes brought about by chromosomal instability (CIN) contribute to tumor heterogeneity, drug resistance, and treatment failure. Whole-chromosome and segmental aneuploidies resulting from CIN have been proposed to allow "macroevolutionary" leaps that may contribute to profound phenotypic change. In this review, we will outline evidence indicating that aneuploidy and CIN contribute to cancer evolution.

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confidence: 99%

The Role of Aneuploidy in Cancer Evolution

Sansregret

Swanton

2016

Cold Spring Harb Perspect Med

215

163

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“…Such whole-chromosomal instability (wCIN) can promote gains of extra copies of oncogenes or losses of tumor-suppressor genes, and it allows selection of karyotypes that thrive in certain environments. Tumor relapse following the initial success of anticancer therapies, as well as anticancer drug resistance, has therefore been attributed to wCIN ( 1 ). Although the wCIN phenotype is of benefi t to the survival of a tumor cell population, too many mistakes in chromosome segregation are lethal.…”

Section: Collateral Genome Instability By Dna Damage In Mitosismentioning

confidence: 99%

“…Nannette Jelluma 1,2 and Geert J.P.L. Kops 1,2,3 Summary: Chromosome segregation errors and DNA damage are in a vicious cycle in cancer cells.…”

Section: Collateral Genome Instability By Dna Damage In Mitosismentioning

confidence: 99%

“…Kops 1,2,3 Summary: Chromosome segregation errors and DNA damage are in a vicious cycle in cancer cells. Bakhoum and colleagues show that the molecular response to damaged DNA during mitosis impairs the chromosome segregation machinery, adding a new level to the already dangerous relations between different kinds of genomic instability.…”

Section: Collateral Genome Instability By Dna Damage In Mitosismentioning

confidence: 99%

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Collateral Genome Instability by DNA Damage in Mitosis

Jelluma

Kops

2014

Cancer Discovery

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only one of the daughter cells after mitosis. Another cause of wCIN is replication stress, a term that signifi es the response to DNA damage caused by stalled replication forks. The mechanism for this is unknown, but alleviation of replication stress in colorectal cancers that display wCIN reduced chromosome segregation errors in a recent study ( 3 ). Conversely, DNA can become damaged as a result of errors in chromosome segregation. The most frequently observed errors in cancer cell lines are chromosomes that lag behind the separating packs of chromosomes at anaphase ( 4 ). These laggards can acquire damage during cytokinesis, resulting in deletions and chromosomal translocations in daughter cells ( 5 ). These and other types of missegregated chromosomes also form micronuclei, structures often used as a marker in cancer diagnosis. Micronuclei suffer from replication stress and damaged DNA ( 6 ). The obvious result of the causal connections between errors in chromosome segregation and DNA damage is a vicious cycle: wCIN can cause DNA damage, which in turn can cause wCIN, and so on and so forth ( Fig. 1 ). It is not diffi cult to see that such a cycle may contribute in important ways to tumor heterogeneity and rapid evolution of the tumor cell population.In this issue of Cancer Discovery , Bakhoum and colleagues ( 7 ) report a surprising novel connection between DNA damage and wCIN. They investigated the consequences of damaging DNA during mitosis and observed an elevated frequency of chromosome missegregations in cancer cells as well as in immortalized normal human cells. The type of missegregation most frequently observed was that of lagging chromosomes. These laggards are the result of hyperstabilization of chromosome-spindle connections and escape detection by the main mitotic cell-cycle checkpoint. Bakhoum and colleagues show that activation of the ATM-CHK2 pathway was responsible for this hyperstabilization, at least in part via the well-known spindle regulators Aurora A and PLK1. Chemical inhibition of ATM, CHK2, Aurora A, or PLK1 prevented not only hyperstability of chromosome-spindle connections but also the increase in lagging chromosomes following mitotic DNA damage. Finally, the authors observed that cell lines most responsive to CHK2 inhibitors (with regard to reducing the frequency of lagging chromosomes) were generally the ones with the highest level of mitotic DDR pathway activation.This new study raises a number of questions related to (cancer) cell biology and cancer therapy. From a molecular mechanistic view, it will be of interest to examine how the mitotic Cancer Discov; 4(11); 1256-8.

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“…Indeed, at least two out of three cancers exhibit aneuploidy [1][2][3]. Although it has been shown that aneuploidy causes stress and reduces cellular itness [4][5][6][7], cancer cells have somehow found a way to cope with aneuploidy and manage to proliferate despite the detrimental consequences of aneuploidy.…”

Section: Introductionmentioning

confidence: 99%

Does Aneuploidy in the Brain Play a Role in Neurodegenerative Disease?

Bos¹,

Spierings²,

Foijer³

et al. 2017

Chromosomal Abnormalities - A Hallmark Manifestation of Genomic Instability

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Aneuploidy, a state in which cells exhibit copy number changes of (parts of) chromosomes, is a hallmark of cancer cells and, when present in all cells, leads to miscarriages and congenital disorders, such as Down syndrome. In addition to these well-known roles of aneuploidy, chromosome copy number changes have also been reported in some studies to occur in neurons in healthy human brain and possibly even more in Alzheimer's disease (AD). However, the studies of aneuploidy in the human brain are currently under debate as earlier indings, mostly based on in situ hybridization approaches, could not be reproduced by more recent single cell sequencing studies with a much higher resolution. Here, we review the various studies on the occurrence of aneuploidy in brain cells from normal individuals and Alzheimer's patients. We discuss possible mechanisms for the origin of aneuploidy and the pros and cons of diferent techniques used to study aneuploidy in the brain, and we provide a future perspective.

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The cancer biology of whole-chromosome instability

Cited by 114 publications

References 155 publications

The Role of Aneuploidy in Cancer Evolution

The Role of Aneuploidy in Cancer Evolution

Collateral Genome Instability by DNA Damage in Mitosis

Does Aneuploidy in the Brain Play a Role in Neurodegenerative Disease?

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