The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity

Tijhuis, Andréa E.; Johnson, Sarah C.; McClelland, Sarah E.

doi:10.1186/s13039-019-0429-1

Cited by 90 publications

(57 citation statements)

References 238 publications

(257 reference statements)

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“…It also suggests that the goal of eliminating cancer in our generation is not realistic [ 2 ]. There are many examples of such a trade-off: a large portion of liver cells change their normal karyotype to polyploidy for the liver tissue’s function; antibody production can also introduce genome-level changes outside the antibody-specific region [ 46 ]; inflammation is necessary for response to injury and infection, but is also linked to chromosomal changes, including aneuploidy [ 47 ]. All of these trade-offs, reflected in genome-level alterations, contribute to and reflect CIN.…”

Section: Cin: a Necessary Evilmentioning

confidence: 99%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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When discussing chromosomal instability, most of the literature focuses on the characterization of individual molecular mechanisms. These studies search for genomic and environmental causes and consequences of chromosomal instability in cancer, aiming to identify key triggering factors useful to control chromosomal instability and apply this knowledge in the clinic. Since cancer is a phenomenon of new system emergence from normal tissue driven by somatic evolution, such studies should be done in the context of new genome system emergence during evolution. In this perspective, both the origin and key outcome of chromosomal instability are examined using the genome theory of cancer evolution. Specifically, chromosomal instability was linked to a spectrum of genomic and non-genomic variants, from epigenetic alterations to drastic genome chaos. These highly diverse factors were then unified by the evolutionary mechanism of cancer. Following identification of the hidden link between cellular adaptation (positive and essential) and its trade-off (unavoidable and negative) of chromosomal instability, why chromosomal instability is the main player in the macro-cellular evolution of cancer is briefly discussed. Finally, new research directions are suggested, including searching for a common mechanism of evolutionary phase transition, establishing chromosomal instability as an evolutionary biomarker, validating the new two-phase evolutionary model of cancer, and applying such a model to improve clinical outcomes and to understand the genome-defined mechanism of organismal evolution.

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Section: Cin: a Necessary Evilmentioning

confidence: 99%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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“…Decades of fundamental and clinical research have shown that CIN has tremendous implications in cancer development, progression, and clinical outcomes ( Figure 1). For example, CIN is associated with cellular transformation [9,50], tumor evolution and progression including intertumoral and intratumoral heterogeneity [51][52][53], metastasis [54][55][56], and the acquisition of drug resistance [57,58]. Thus, it is perhaps unsurprising that the presence of CIN is typically associated with worse patient outcomes [59][60][61][62].…”

Section: The Impact Of Cin On Cancer Development and Progressionmentioning

confidence: 99%

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

Vishwakarma

McManus

2020

Cancers

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Chromosome instability (CIN) refers to an ongoing rate of chromosomal changes and is a driver of genetic, cell-to-cell heterogeneity. It is an aberrant phenotype that is intimately associated with cancer development and progression. The presence, extent, and level of CIN has tremendous implications for the clinical management and outcomes of those living with cancer. Despite its relevance in cancer, there is still extensive misuse of the term CIN, and this has adversely impacted our ability to identify and characterize the molecular determinants of CIN. Though several decades of genetic research have provided insight into CIN, the molecular determinants remain largely unknown, which severely limits its clinical potential. In this review, we provide a definition of CIN, describe the two main types, and discuss how it differs from aneuploidy. We subsequently detail its impact on cancer development and progression, and describe how it influences metastatic potential with reference to cancer prognosis and outcomes. Finally, we end with a discussion of how CIN induces genetic heterogeneity to influence the use and efficacy of several precision medicine strategies, including patient and risk stratification, as well as its impact on the acquisition of drug resistance and disease recurrence.

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“…Chromosomal instability (CIN) is a type of genomic instability that is defined by the loss or rearrangement of chromosomes that classifies numerical CIN or structural CIN [ 1 ]. Defects in several cellular processes, including cell-cycle checkpoint controls, chromosome segregation, DNA repair and DNA replication are known to cause CIN [ 2 , 3 , 4 ]. The spectrum of gene alterations and mutations that cause CIN is only partially known, but insights would be beneficial for the treatment of tumors with high CIN (CIN + ).…”

Section: Introductionmentioning

confidence: 99%

Exploiting Chromosomal Instability of PTEN-Deficient Triple-Negative Breast Cancer Cell Lines for the Sensitization Against PARP1 Inhibition in a Replication-Dependent Manner

Meyer

Classen

Zielinski

et al. 2020

Cancers

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Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog (PTEN) as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype. In silico analysis of mRNA expression data from 200 TNBC patients revealed low expression of PTEN in tumors with a high CIN70 score. Western blot analysis of TNBC cell lines confirm lower protein expression of PTEN compared to non TNBC cell lines. Further, PTEN-deficient cell lines showed cellular sensitivity towards PARP1 inhibition treatment. DNA fiber assays and examination of chromatin bound protein fractions indicate a protective role of PTEN at stalled replication forks. In this study, we recognize PTEN as a potential CIN-causing gene in TNBC and identify its important role in the replication processes.

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The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity

Cited by 90 publications

References 238 publications

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

Exploiting Chromosomal Instability of PTEN-Deficient Triple-Negative Breast Cancer Cell Lines for the Sensitization Against PARP1 Inhibition in a Replication-Dependent Manner

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