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Triggering Forces of Chromosome Instability
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Triggering Forces of Chromosome Instability

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 19654

Special Issue Editors

Prof. Dr. Patrice Carde

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Guest Editor
Département d’hématologie, Gustave Roussy Cancer Campus, Université Paris Saclay, 94808 Villejuif, France
Interests: clinical onco-hematology; lymphoma; chromosomal instability; telomeres
Special Issues, Collections and Topics in MDPI journals
Dr. Eric Jeandidier

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Guest Editor
Department of Genetic , Emile Muller Hospital, 68070 Mulhouse ,France
Dr. Steffen Junker

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Guest Editor
Institute of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark
Dr. Radhia M'kacher

E-Mail Website
Guest Editor
Cell Environment, Genopole, Evry, France
Interests: cytogenetics; telomere; DNA repair; radiation effects; genotoxic stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chromosomal instability has proven an essential biomarker for the management of patients with cancer, inflammatory diseases, and of individuals in otherwise healthy populations exposed to genotoxic agents, and of their progeny.

Chromosomal instability is defined as the progressive accumulation of numerical and structural chromosomal anomalies.

Ample evidence acquired during the past decades has demonstrated the predictive and prognostic value of chromosomal instability as a biomarker for treatment response and clinical outcomes in these populations.

Substantial progress has been achieved for the detection and identification of chromosomal instability, and cytogenetic analyses have, until now, remained the most precise and reliable techniques utilized. However, genomic analyses have lately made a sensational entrance into the clinic.

In spite of the achievements applying chromosomal instability as biomarkers in the clinic, the development and standardization of the approaches for their detection are still required for the use of this concept in personalized medicine.

This Special Issue in Genes, entitled  “Triggering Forces of Chromosomal Instability”, gathers original research papers and review papers on the development of novel approaches for the detection of chromosomal instability, on the underlying mechanisms leading to chromosome instability in different populations , on implications of chromosomal instability in the clinical outcomes of patients, and finally, on the use of insights into chromosomal instability mechanisms to design novel and specific therapeutic interventions that may improve future treatments.

Prof. Patrice P. Carde
Dr Eric Jeandidier
Dr Steffen Junker
Dr Radhia M'kacher
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chromosomal instability
  • DNA repair
  • telomere
  • senescence
  • aging
  • cancer
  • microenvironment
  • inflammation
  • viral infection
  • genotoxic agents
  • clinical outcome
  • treatment

Published Papers (5 papers)

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Research

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12 pages, 6140 KiB  
Article
A Central Role of Telomere Dysfunction in the Formation of a Unique Translocation within the Sub-Telomere Region Resulting in Duplication and Partial Trisomy
by Radhia M’Kacher, Marguerite Miguet, Pierre-Yves Maillard, Bruno Colicchio, Sophie Scheidecker, Wala Najar, Micheline Arnoux, Noufissa Oudrhiri, Claire Borie, Margaux Biehler, Andreas Plesch, Leonhard Heidingsfelder, Annelise Bennaceur-Griscelli, Alain Dieterlen, Philippe Voisin, Steffen Junker, Patrice Carde and Eric Jeandidier
Genes 2022, 13(10), 1762; https://doi.org/10.3390/genes13101762 - 29 Sep 2022
Cited by 1 | Viewed by 1488
Abstract
Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal [...] Read more.
Telomeres play a major role in maintaining genome stability and integrity. Putative involvement of telomere dysfunction in the formation of various types of chromosomal aberrations is an area of active research. Here, we report a case of a six-month-old boy with a chromosomal gain encompassing the 11q22.3q25 region identified by SNP array analysis. The size of the duplication is 26.7 Mb and contains 170 genes (OMIM). The duplication results in partial trisomy of the region in question with clinical consequences, including bilateral renal dysplasia, delayed development, and a heart defect. Moreover, the karyotype determined by R-banding and chromosome painting as well as by hybridization with specific sub-telomere probes revealed the presence of an unbalanced t(9;11)(p24;q22.3) translocation with a unique breakpoint involving the sub-telomere region of the short arm of chromosome 9. The karyotypes of the parents were normal. Telomere integrity in circulating lymphocytes from the child and from his parents was assessed using an automated high-throughput method based on fluorescence in situ hybridization (FISH) with telomere- and centromere-specific PNA probes followed by M-FISH multicolor karyotyping. Very short telomeres, as well as an increased frequency of telomere loss and formation of telomere doublets, were detected in the child’s cells. Interestingly, similar telomere profiles were found in the circulating lymphocytes of the father. Moreover, an assessment of clonal telomere aberrations identified chromosomes 9 and 11 with particularly high frequencies of such aberrations. These findings strongly suggest that telomere dysfunction plays a central role in the formation of this specific unbalanced chromosome rearrangement via chromosome end-to-end fusion and breakage–fusion–bridge cycles. Full article
(This article belongs to the Special Issue Triggering Forces of Chromosome Instability)
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19 pages, 11825 KiB  
Article
Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome
by Noufissa Oudrhiri, Radhia M’kacher, Diana Chaker, Bruno Colicchio, Claire Borie, Eric Jeandidier, Alain Dieterlen, Frank Griscelli, Annelise Bennaceur-Griscelli and Ali G. Turhan
Genes 2022, 13(8), 1395; https://doi.org/10.3390/genes13081395 - 05 Aug 2022
Cited by 3 | Viewed by 1830
Abstract
Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1–STN1–TEN1 [...] Read more.
Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (CTC1). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1–STN1–TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how CTC1 mutations may have an effect on telomere structure and function. For that purpose, we established the very first induced pluripotent stem cell lines (iPSCs) from a compound heterozygous patient with CP carrying deleterious mutations in both alleles of CTC1. Telomere dysfunction and chromosomal instability were assessed in both circulating lymphocytes and iPSCs from the patient and from healthy controls of similar age. The circulating lymphocytes and iPSCs from the CP patient were characterized by their higher telomere length heterogeneity and telomere aberrations compared to those in control cells from healthy donors. Moreover, in contrast to iPSCs from healthy controls, the high levels of telomerase were associated with activation of the alternative lengthening of telomere (ALT) pathway in CP-iPSCs. This was accompanied by inappropriate activation of the DNA repair proteins γH2AX, 53BP1, and ATM, as well as with accumulation of DNA damage, micronuclei, and anaphase bridges. CP-iPSCs presented features of cellular senescence and increased radiation sensitivity. Clonal dicentric chromosomes were identified only in CP-iPSCs after exposure to radiation, thus mirroring the role of telomere dysfunction in their formation. These data demonstrate that iPSCs derived from CP patients can be used as a model system for molecular studies of the CP syndrome and underscores the complexity of telomere dysfunction associated with the defect of DNA repair machinery in the CP syndrome. Full article
(This article belongs to the Special Issue Triggering Forces of Chromosome Instability)
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17 pages, 6379 KiB  
Article
Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility
by Radhia M’kacher, Bruno Colicchio, Claire Borie, Steffen Junker, Valentine Marquet, Leonhard Heidingsfelder, Kevin Soehnlen, Wala Najar, William M. Hempel, Noufissa Oudrhiri, Nadège Wilhelm-Murer, Marguerite Miguet, Micheline Arnoux, Catherine Ferrapie, Wendy Kerbrat, Andreas Plesch, Alain Dieterlen, Theodore Girinsky, Philippe Voisin, Georges Deschenes, Anne-Claude Tabet, Catherine Yardin, Annelise Bennaceur-Griscelli, Michael Fenech, Patrice Carde and Eric Jeandidieradd Show full author list remove Hide full author list
Genes 2020, 11(5), 475; https://doi.org/10.3390/genes11050475 - 27 Apr 2020
Cited by 16 | Viewed by 4083
Abstract
Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and [...] Read more.
Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10−4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic. Full article
(This article belongs to the Special Issue Triggering Forces of Chromosome Instability)
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Review

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13 pages, 2118 KiB  
Review
Cytokinesis-Block Micronucleus Cytome Assay Evolution into a More Comprehensive Method to Measure Chromosomal Instability
by Michael Fenech
Genes 2020, 11(10), 1203; https://doi.org/10.3390/genes11101203 - 15 Oct 2020
Cited by 66 | Viewed by 7408
Abstract
This review describes the cytokinesis-block micronucleus (CBMN) cytome assay and its evolution into a molecular cytogenetic method of chromosomal instability (CIN). Micronuclei (MNi) originate from whole chromosomes or chromosome fragments that fail to segregate to the poles of the cell during mitosis. These [...] Read more.
This review describes the cytokinesis-block micronucleus (CBMN) cytome assay and its evolution into a molecular cytogenetic method of chromosomal instability (CIN). Micronuclei (MNi) originate from whole chromosomes or chromosome fragments that fail to segregate to the poles of the cell during mitosis. These lagging chromosomes are excluded from the daughter nuclei and are enveloped in their own membrane to form MNi. The CBMN assay was developed to allow MNi to be scored exclusively in once-divided binucleated cells, which enables accurate measurement of chromosome breakage or loss without confounding by non-dividing cells that cannot express MNi. The CBMN assay can be applied to cell lines in vitro and cells such as lymphocytes that can be stimulated to divide ex vivo. In the CBMN assay, other CIN biomarkers such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are also measured. Use of centromere, telomere, and chromosome painting probes provides further insights into the mechanisms through which MNi, NPBs and NBUDs originate. Measurement of MNi is also important because entrapment within a micronucleus may cause chromosomes to shatter and, after nuclear reintegration, become rearranged. Additionally, leakage of DNA from MNi can stimulate inflammation via the cyclic GMP-AMP Synthase—Stimulator of Interferon Genes (cGAS-STING) DNA sensing mechanism of the innate immune system. Full article
(This article belongs to the Special Issue Triggering Forces of Chromosome Instability)
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Other

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13 pages, 807 KiB  
Perspective
Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival
by Christine J. Ye, Zachary Sharpe and Henry H. Heng
Genes 2020, 11(10), 1162; https://doi.org/10.3390/genes11101162 - 30 Sep 2020
Cited by 24 | Viewed by 3778
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Triggering Forces of Chromosome Instability)
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