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      Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes

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          Abstract

          Chromosome instability (CIN), or continual changes in chromosome complements, is an enabling feature of cancer; however, the molecular determinants of CIN remain largely unknown. Emerging data now suggest that aberrant sister chromatid cohesion may induce CIN and contribute to cancer. To explore this possibility, we employed clinical and fundamental approaches to systematically assess the impact reduced cohesion gene expression has on CIN and cancer. Ten genes encoding critical functions in cohesion were evaluated and remarkably, each exhibits copy number losses in 12 common cancer types, and reduced expression is associated with worse patient survival. To gain mechanistic insight, we combined siRNA-based silencing with single cell quantitative imaging microscopy to comprehensively assess the impact reduced expression has on CIN in two karyotypically stable cell lines. We show that reduced expression induces CIN phenotypes, namely increases in micronucleus formation and nuclear areas. Subsequent direct tests involving a subset of prioritized genes also revealed significant changes in chromosome numbers with corresponding increases in moderate and severe cohesion defects within mitotic chromosome spreads. Collectively, our clinical and fundamental findings implicate reduced sister chromatid cohesion, resulting from gene copy number losses, as a key pathogenic event in the development and progression of many cancer types.

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          Most cited references 54

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

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              The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

              The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. © 2012 AACR.
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                Author and article information

                Contributors
                Kirk.McManus@umanitoba.ca
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                17 January 2020
                17 January 2020
                2020
                : 10
                Affiliations
                [1 ]ISNI 0000 0004 1936 9609, GRID grid.21613.37, Department of Biochemistry & Medical Genetics, , University of Manitoba, ; Winnipeg, Manitoba R3E 0J9 Canada
                [2 ]ISNI 0000 0001 0701 0170, GRID grid.419404.c, Research Institute in Oncology & Hematology, , CancerCare Manitoba, ; Winnipeg, Manitoba R3E 0V9 Canada
                Article
                57530
                10.1038/s41598-020-57530-9
                6969069
                31953484
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                © The Author(s) 2020

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                cancer imaging, cancer genetics

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