A Double-Edged Sword: How Oncogenes and Tumor Suppressor Genes Can Contribute to Chromosomal Instability

Orr, Bernardo; Compton, Duane A.

doi:10.3389/fonc.2013.00164

Cited by 72 publications

(80 citation statements)

References 180 publications

(202 reference statements)

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“…Activation of oncogenic pathways, loss of key tumor suppressor pathways, and a large number of therapeutic interventions can either facilitate or induce CIN (Orr and Compton 2013;Lee et al 2016). This vulnerability stands in sharp contrast to the lack of aberrant karyotypes observed in normal human cells (Knouse et al 2014).…”

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

128

103

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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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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

128

103

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“…There is growing evidence that oncogenic signaling pathways, which are universally dysregulated in cancer, not only drive unrestrained cell proliferation and resistance to apoptosis, but also contribute to CIN and aneuploidy. 13 However, the precise mechanisms by which oncogenic signaling events alter the function of mitosis or cytokinesis regulators remain poorly understood. We have shown previously that hyperactivation of the ERK1/2 MAPK pathway induces tetraploidization of intestinal epithelial cells, enhancing their tumorigenic potential.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Several observations suggest that oncogenic Ras signaling may contribute to cancer progression by promoting genomic instability. 13,14 Overexpression of oncogenic Ras mutants in various model cell lines was shown to promote chromosome mis-segregation, centrosome amplification, ploidy changes, and induction of CIN. Oncogenic Ras also increases aneuploidization in mice.…”

Section: Discussionmentioning

confidence: 99%

“…3 The mechanisms that cause tetraploidy and aneuploidy are not clear but accumulating evidence points to a role of oncogenic signaling pathways. 13 Specifically, hyperactive Ras signaling has been implicated in the induction of CIN but the precise molecular mechanisms involved remain unknown. 13,14 We have recently reported that oncogenic Ras or sustained nuclear MEK/ERK1/2 signaling induces tetraploidization of epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

“…13 Specifically, hyperactive Ras signaling has been implicated in the induction of CIN but the precise molecular mechanisms involved remain unknown. 13,14 We have recently reported that oncogenic Ras or sustained nuclear MEK/ERK1/2 signaling induces tetraploidization of epithelial cells. 10 Here, we investigated the molecular basis of this oncogenic response.…”

Section: Introductionmentioning

confidence: 99%

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Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway

et al. 2016

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Aneuploidy is a common feature of human solid tumors and is often associated with poor prognosis. There is growing evidence that oncogenic signaling pathways, which are universally dysregulated in cancer, contribute to the promotion of aneuploidy. However, the mechanisms connecting signaling pathways to the execution of mitosis and cytokinesis are not well understood. Here, we show that hyperactivation of the ERK1/2 MAP kinase pathway in epithelial cells impairs cytokinesis, leading to polyploidization and aneuploidy. Mechanistically, deregulated ERK1/2 signaling specifically downregulates expression of the Fbox protein Fbxw7b, a substrate-binding subunit of the SCF Fbxw7 ubiquitin ligase, resulting in the accumulation of the mitotic kinase Aurora A. Reduction of Aurora A levels by RNA interference or pharmacological inhibition of MEK1/2 reverts the defect in cytokinesis and decreases the frequency of abnormal cell divisions induced by oncogenic H-Ras V12 . Reciprocally, overexpression of Aurora A or silencing of Fbxw7b phenocopies the effect of H-Ras V12 on cell division. In vivo, conditional activation of MEK2 in the mouse intestine lowers Fbxw7b expression, resulting in the accumulation of cells with enlarged nuclei. We propose that the ERK1/2/ Fbxw7b/Aurora A axis identified in this study contributes to genomic instability and tumor progression.

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Cytogenetic signatures of recurrent pregnancy losses

et al. 2020

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Objectives To investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL) and to determine biological mechanisms contributing to RPL. Methods During a 20‐year period, 12 096 POC samples underwent classical chromosome analysis. Cytogenetic findings were compared between the SM and RPL cohorts. Results Analysis of RPL cohort has identified an increased incidence of inherited and de novo structural chromosome abnormalities, recurrent polyploid conceptions, and complex mosaic alterations. These abnormalities are the signature of genomic instability, posing a high risk of genetic abnormalities to offspring independent of maternal age. Predominance of male conceptions in the RPL cohort points toward an X‐linked etiology and gender‐specific intolerance for certain genetic abnormalities. Conclusions Our study showed several possible genetic etiologies of RPL, including parental structural chromosome rearrangements, predisposition to meiotic nondisjunction, and genomic instability. Loss of karyotypically normal fetuses might be attributed to defects in genes essential for fetal development, as well as aberrations affecting the X chromosome. Molecular studies of parental and POC genomes will help to identify inherited defects in genes involved in meiotic divisions and DNA repair to confirm our hypotheses, and to discover novel fetal‐essential genes.

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A Double-Edged Sword: How Oncogenes and Tumor Suppressor Genes Can Contribute to Chromosomal Instability

Cited by 72 publications

References 180 publications

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway

Cytogenetic signatures of recurrent pregnancy losses

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