Cancer Karyotypes: Survival of the Fittest

Nicholson, Joshua M.; Cimini, Daniela

doi:10.3389/fonc.2013.00148

Cited by 55 publications

(63 citation statements)

References 125 publications

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“…The authors argue that at “a certain time point when cells have acquired a chromosome composition that provides appropriate growth advantage in culture, maintenance of the chromosome composition becomes a selection force.” Evidence of genomic convergence was also found in the context of prostate cancer [52]. In [41], CIN and aneuploidy of cells have been studied. It was shown that once diploid cells become aneuploid, they also appear to become chromosomally stable, which provides a mechanism of instability reversal, see also [3].…”

Section: Discussionmentioning

confidence: 99%

Evolution of genetic instability in heterogeneous tumors

Asatryan

Komarova

2016

Journal of Theoretical Biology

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Genetic instability is an important characteristic of cancer. While most cancers develop genetic instability at some stage of their progression, sometimes a temporary rise of instability is followed by the return to a relatively stable genome. Neither the reasons for these dynamics, nor, more generally, the role of instability in tumor progression, are well understood. In this paper we develop a class of mathematical models to study the evolutionary competition dynamics among different sub-populations in a heterogeneous tumor. We observe that despite the complexity of this multi-component and multi-process system, there is only a small number of scenarios expected in the context of the evolution of instability. If the penalty incurred by unstable cells (the decrease in the growth due to deleterious mutations) is high compared with the gain (the production rate of advantageous mutations), then instability does not evolve. In the opposite case, instability evolves and comes to dominate the system. In the intermediate parameter regime, instability is generated but later gives way to stable clones. Moreover, the model also informs us of the patterns of instability for cancer lineages corresponding to different stages of progression. It is predicted that mutations causing instability are merely “passengers” in tumors that have undergone only a small number of malignant mutations. Further down the path of carcinogenesis, however, unstable cells are more likely to give rise to the winning clonal wave that takes over the tumor and carries the evolution forward, thus conferring a causal role of the instability in such cases. Further, each individual clonal wave (i.e. cells harboring a fixed number of malignant driver mutations) experiences its own evolutionary history. It can fall under one of three types of temporal behavior: stable throughout, unstable to stable, or unstable throughout. Which scenario is realized depends on the subtle (but predictable) interplay among mutation rates and the death toll associated with the instability. The modeling approach provided here sheds light onto important aspects of the evolutionary dynamics of instability, which may be relevant to treatment scenarios that target instability or damage repair.

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Section: Discussionmentioning

confidence: 99%

Evolution of genetic instability in heterogeneous tumors

Asatryan

Komarova

2016

Journal of Theoretical Biology

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“…In consequence, merotelic attachment is considered to be a major cause of CIN [47]. The incidence of lagging chromosomes in cancer cells exhibiting CIN is 10-60% [3]. Most lagging chromosomes eventually segregate properly, but sometimes they may be segregated to the wrong pole, giving rise to aneuploidy (Fig.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…1). Genetic heterogeneity resulting from CIN is supposedly followed by selective outgrowth of cells that have a growth advantage in a given (micro)environment [3]. Whole sequencing of cancer genomes revealed the tendency for oncogene-rich chromosomal regions to be amplified, and tumor suppressor gene-rich chromosomal regions lost [140].…”

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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“…C hromosome instability (CIN), defined by an elevated rate of chromosome missegregation and breakage, results in diverse chromosome abnormalities in tumor cell populations (1)(2)(3)(4)(5)(6)(7). Accumulating cytogenetic analyses of more than 60,000 cases of human cancer have indicated that most of the solid tumors contain chromosome aberrations, with each tumor displaying a distinct abnormal karyotype (Mitelman database: cgap.nci.nih.gov/ Chromosomes/Mitelman).…”

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confidence: 99%

Chromosome instability drives phenotypic switching to metastasis

Gao

Koeman

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chromosome instability (CIN) is the most striking feature of human cancers. However, how CIN drives tumor progression to metastasis remains elusive. Here we studied the role of chromosome content changes in generating the phenotypic dynamics that are required for metastasis. We isolated epithelial and mesenchymal clones from human carcinoma cell lines and showed that the epithelial clones were able to generate mesenchymal variants, which had the potential to further produce epithelial revertants autonomously. The successive acquisition of invasive mesenchymal and then epithelial phenotypes recapitulated the steps in tumor progression to metastasis. Importantly, the generation of mesenchymal variants from clonal epithelial populations was associated with subtle changes in chromosome content, which altered the chromosome transcriptome and influenced the expression of genes encoding intercellular junction (IJ) proteins, whereas the loss of chromosome 10p, which harbors the ZEB1 gene, was frequently detected in epithelial variants generated from mesenchymal clones. Knocking down these IJ genes in epithelial cells induced a mesenchymal phenotype, whereas knocking down the ZEB1 gene in mesenchymal cells induced an epithelial phenotype, demonstrating a causal role of chromosome content changes in phenotypic determination. Thus, our studies suggest a paradigm of tumor metastasis: primary epithelial carcinoma cells that lose chromosomes harboring IJ genes acquire an invasive mesenchymal phenotype, and subsequent chromosome content changes such as loss of 10p in disseminated mesenchymal cells generate epithelial variants, which can be selected for to generate epithelial tumors during metastatic colonization.tumor metastasis | chromosome instability | aneuploidy | clonal evolution | epithelial-mesenchymal transition (E-MT) C hromosome instability (CIN), defined by an elevated rate of chromosome missegregation and breakage, results in diverse chromosome abnormalities in tumor cell populations (1-7). Accumulating cytogenetic analyses of more than 60,000 cases of human cancer have indicated that most of the solid tumors contain chromosome aberrations, with each tumor displaying a distinct abnormal karyotype (Mitelman database: cgap.nci.nih.gov/ Chromosomes/Mitelman). In typical human cancers, one-quarter of the genome was affected by arm-level copy-number aberrations (8). Moreover, cancer genome sequencing revealed dynamic chromosome content changes during clonal evolution of the tumor cell population (9-12). However, how chromosome loss or gain drives tumor progression to metastasis remains elusive (13-17). Tumor metastasis is a multistep process, with the acquisition of an invasive mesenchymal phenotype being a crucial step for tumor dissemination, as is the reacquisition of an epithelial phenotype for metastatic colonization (18,19). Although clonal evolution theory has been well established as a general mechanism of tumor progression (16,20), how it contributes to the sequential phenotype acquisition leading to metastasis...

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Cancer Karyotypes: Survival of the Fittest

Cited by 55 publications

References 125 publications

Evolution of genetic instability in heterogeneous tumors

Evolution of genetic instability in heterogeneous tumors

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

Chromosome instability drives phenotypic switching to metastasis

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