The mitotic origin of chromosomal instability

Bakhoum, Samuel F.; Silkworth, William T.; Nardi, Isaac K.; Nicholson, Joshua M.; Compton, Duane A.; Cimini, Daniela

doi:10.1016/j.cub.2014.01.019

Cited by 116 publications

(94 citation statements)

References 10 publications

(19 reference statements)

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“…As loss of mitotic fidelity is the prime cause of CIN [147], identification of molecular defects or alterations in mitotic control must be an essential step towards development of anti-mitotic drugs.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Section: Accepted Manuscriptmentioning

confidence: 99%

Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…For Darwinian selection to occur, tumor cells must preserve the aptitude to maintain phenotypic heterogeneity through genomic instability (Yates and Campbell, 2012). A prevalent, yet understudied, form of instability is numerical (whole) chromosomal instability, whereby cancer cells rapidly vary the number of chromosome copies (karyotype) through whole-chromosome missegregation during mitosis (Bakhoum et al, 2014b;Lengauer et al, 1997). This karyotypic heterogeneity engenders transcriptomic and proteomic imbalance (Pavelka et al, 2010b;Stingele et al, 2012;Upender et al, 2004).…”

Section: Introductionmentioning

confidence: 96%

Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution

Laughney¹,

Elizalde²,

Genovese³

et al. 2015

Cell Reports

106

111

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Numerical chromosomal instability is a ubiquitous feature of human neoplasms. Due to experimental limitations, fundamental characteristics of karyotypic changes in cancer are poorly understood. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we show that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimizes phenotypic heterogeneity and clonal survival. Departure from this range reduces clonal fitness and limits subclonal diversity. Mapping of the aneuploid fitness landscape reveals a highly favorable, commonly observed, near-triploid state onto which evolving diploid- and tetraploid-derived populations spontaneously converge, albeit at a much lower fitness cost for the latter. Finally, by analyzing 1,368 chromosomal translocation events in five human cancers, we find that karyotypic evolution also shapes chromosomal translocation patterns by selecting for more oncogenic derivative chromosomes. Thus, chromosomal instability can generate the heterogeneity required for Darwinian tumor evolution.

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“…Irrespective of the underlying cause, these mechanisms converge onto the process of chromosome segregation during mitosis, and lead to lagging chromosomes during anaphase, which is considered a hallmark of chromosomally unstable cells (Fig. 1B) (Cimini et al 2001;Thompson and Compton 2011;Bakhoum et al 2014b). Chromosomes lag as a result of their simultaneous attachments to microtubules emanating from opposite spindle poles (Cimini et al 2003(Cimini et al , 2002, which increases their potential for missegregation or encapsulation in micronuclei (Crasta et al 2012).…”

Section: The Origins Of Cinmentioning

confidence: 99%

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Bakhoum

Landau

2017

Cold Spring Harb Perspect Med

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114

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Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.

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The mitotic origin of chromosomal instability

Cited by 116 publications

References 10 publications

Chromosomal instability: A common feature and a therapeutic target of cancer

Chromosomal instability: A common feature and a therapeutic target of cancer

Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

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