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      Aneuploidy: Cancer strength or vulnerability?

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          Abstract

          Aneuploidy is a very rare and tissue‐specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age‐related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell‐like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy‐tolerating mechanisms as cancer vulnerability.

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          Most cited references185

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          Effects of aneuploidy on cellular physiology and cell division in haploid yeast.

          Aneuploidy is a condition frequently found in tumor cells, but its effect on cellular physiology is not known. We have characterized one aspect of aneuploidy: the gain of extra chromosomes. We created a collection of haploid yeast strains that each bear an extra copy of one or more of almost all of the yeast chromosomes. Their characterization revealed that aneuploid strains share a number of phenotypes, including defects in cell cycle progression, increased glucose uptake, and increased sensitivity to conditions interfering with protein synthesis and protein folding. These phenotypes were observed only in strains carrying additional yeast genes, which indicates that they reflect the consequences of additional protein production as well as the resulting imbalances in cellular protein composition. We conclude that aneuploidy causes not only a proliferative disadvantage but also a set of phenotypes that is independent of the identity of the individual extra chromosomes.
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            The Molecular Biology of Spindle Assembly Checkpoint Signaling Dynamics.

            The spindle assembly checkpoint is a safeguard mechanism that coordinates cell-cycle progression during mitosis with the state of chromosome attachment to the mitotic spindle. The checkpoint prevents mitotic cells from exiting mitosis in the presence of unattached or improperly attached chromosomes, thus avoiding whole-chromosome gains or losses and their detrimental effects on cell physiology. Here, I review a considerable body of recent progress in the elucidation of the molecular mechanisms underlying checkpoint signaling, and identify a number of unresolved questions.
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              Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast

              Aneuploidy, referring here to genome contents characterized by abnormal numbers of chromosomes, has been associated with developmental defects, cancer, and adaptive evolution in experimental organisms1–9. However, it remains unresolved how aneuploidy impacts gene expression and whether aneuploidy could directly bring phenotypic variation and improved fitness over that of euploid counterparts. In this work, we designed a novel scheme to generate, through random meiotic segregation, 38 stable and fully isogenic aneuploid yeast strains with distinct karyotypes and genome contents between 1N and 3N without involving any genetic selection. Through phenotypic profiling under various growth conditions or in the presence of a panel of chemotherapeutic or antifungal drugs, we found that aneuploid strains exhibited diverse growth phenotypes, and some aneuploid strains grew better than euploid control strains under conditions suboptimal for the latter. Using quantitative mass spectrometry-based proteomics, we show that the levels of protein expression largely scale with chromosome copy numbers, following the same trend observed for the transcriptome. These results provide strong evidence that aneuploidy directly impacts gene expression at both the transcriptome and proteome levels and can generate significant phenotypic variation that could bring about fitness gains under diverse conditions. Our findings suggest that the fitness ranking between euploid and aneuploid cells is context- and karyotype-dependent, providing the basis for the notion that aneuploidy can directly underlie phenotypic evolution and cellular adaptation.
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                Author and article information

                Contributors
                giorgia.simonetti3@unibo.it
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                0020-7136
                1097-0215
                31 October 2018
                01 January 2019
                : 144
                : 1 ( doiID: 10.1002/ijc.v144.1 )
                : 8-25
                Affiliations
                [ 1 ] Department of Experimental, Diagnostic and Specialty Medicine University of Bologna and Institute of Hematology "L. e A. Seràgnoli" Bologna Italy
                [ 2 ] Scientific Directorate Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS Meldola Italy
                Author notes
                [*] [* ] Correspondence to: Giorgia Simonetti, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna and Institute of Hematology “L. e A. Seràgnoli,” via Massarenti, 9, 40138 Bologna, Italy, E‐mail: giorgia.simonetti3@ 123456unibo.it ; Tel: 0039 0512143791
                Author information
                https://orcid.org/0000-0001-6954-969X
                Article
                IJC31718
                10.1002/ijc.31718
                6587540
                29981145
                57190b10-a550-480b-96ab-9faeff58e582
                © 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 20 February 2018
                : 05 June 2018
                : 14 June 2018
                Page count
                Figures: 3, Tables: 2, Pages: 18, Words: 14952
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro
                Award ID: 19226
                Funded by: European Union Seventh Framework Programme
                Award ID: 306242‐NGS‐PTL
                Award ID: FP7/2007–2013
                Categories
                Mini Review
                Mini Review
                Custom metadata
                2.0
                ijc31718
                1 January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:21.06.2019

                Oncology & Radiotherapy
                aneuploidy,carcinogenesis,cancer therapy,spindle assembly checkpoint
                Oncology & Radiotherapy
                aneuploidy, carcinogenesis, cancer therapy, spindle assembly checkpoint

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