Tetraploidy and CIN: a dangerous combination

Dewhurst, Sally M.; Swanton, Charles

doi:10.1080/15384101.2015.1084208

Cited by 6 publications

(10 citation statements)

References 7 publications

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“…These data again indicated that LMS is driven by a perturbed tumor suppressor network (Fig. 5e ), which gives rise to WGD and gross genomic instability, thereby accelerating tumor evolution, in the majority of cases 19 – 21 .…”

Section: Resultsmentioning

confidence: 74%

Integrative genomic and transcriptomic analysis of leiomyosarcoma

et al. 2018

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Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.

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Section: Resultsmentioning

confidence: 74%

Integrative genomic and transcriptomic analysis of leiomyosarcoma

et al. 2018

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“…In addition to the relationship between tetraploidy and cancer, an unexpected link between tetraploidy and aging has been recently proposed in a mouse model . The tetraploidy‐prone mice had not existed before 2013, partly because whole‐genome doubling leads to spontaneous miscarriages . To overcome this difficulty, we used an alternative strategy in which unscheduled tetraploidy was induced in a tissue‐specific manner .…”

Section: Potential Association Of Tetraploidy With Agingmentioning

confidence: 99%

“…10,11 The tetraploidy-prone mice had not existed before 2013, 10 partly because whole-genome doubling leads to spontaneous miscarriages. 2,9 To overcome this difficulty, we used an alternative strategy in which unscheduled tetraploidy was induced in a tissue-specific manner. 10 Before explaining our strategy, we will Figure 4A,B).…”

Section: Tetraploidy With Agin Gmentioning

confidence: 99%

“…Tetraploidy is commonly seen in a subset of hepatocytes and cardiomyocytes in physiological conditions . Nevertheless, it is an uncommon and unfavorable event in other somatic cells; tetraploid fetuses inevitably result in spontaneous miscarriages . It has been shown that tetraploidization facilitates oncogenic transformation and cancer progression .…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Nevertheless, it is an uncommon and unfavorable event in other somatic cells; tetraploid fetuses inevitably result in spontaneous miscarriages. 2,9 It has been shown that tetraploidization facilitates oncogenic transformation and cancer progression. 3 Furthermore, our unique mouse model has also suggested an unprecedented link between tetraploidy and aging.…”

Section: Introductionmentioning

confidence: 99%

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Tetraploidy in cancer and its possible link to aging

et al. 2018

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Tetraploidy, a condition in which a cell has four homologous sets of chromosomes, is often seen as a natural physiological condition but is also frequently seen in pathophysiological conditions such as cancer. Tetraploidy facilitates chromosomal instability (CIN), which is an elevated level of chromosomal loss and gain that can cause production of a wide variety of aneuploid cells that carry structural and numerical aberrations of chromosomes. The resultant genomic heterogeneity supposedly expedites karyotypic evolution that confers oncogenic potential in spite of the reduced cellular fitness caused by aneuploidy. Recent studies suggest that tetraploidy might also be associated with aging; mice with mutations in an intermediate filament protein have revealed that these tetraploidy‐prone mice exhibit tissue disorders associated with aging. Cellular senescence and its accompanying senescence‐associated secretory phenotype have now emerged as critical factors that link tetraploidy and tetraploidy‐induced CIN with cancer, and possibly with aging. Here, we review recent findings about how tetraploidy is related to cancer and possibly to aging, and discuss underlying mechanisms of the relationship, as well as how we can exploit the properties of cells exhibiting tetraploidy‐induced CIN to control these pathological conditions.

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