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Cancers
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Chromosomal Instability and Cancers
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Chromosomal Instability and Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 44262

Special Issue Editors

Dr. Thomas Ried

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Guest Editor
National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
Interests: molecular cytogenetics; chromosomal instability; colorectal cancer; tumor heterogeneity; tumor evolution; (cancer) stem cells
Dr. Daniela Hirsch

E-Mail
Guest Editor
Institute of Pathology (Mannheim), Heidelberg University, 68167 Mannheim, Germany
Interests: molecular cytogenetics; chromosomal instability; colorectal cancer; tumor heterogeneity; tumor evolution; (cancer) stem cells
Dr. Jordi Camps

E-Mail Website
Guest Editor
Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, 08036 Catalonia, Spain
Interests: molecular cytogenetics; chromosomal instability; colorectal cancer; tumor heterogeneity; tumor evolution; (cancer) stem cells

Special Issue Information

Dear Colleagues,

Cytogenetic abnormalities are a hallmark of cancer cells. Chromosomal alterations in cancer are classified into two groups: structural rearrangements, including translocations, and numerical alterations, i.e., aneuploidy. In carcinomas, numerical aberrations result in a tumor type-specific distribution of genomic copy number alterations. Genomic imbalances occur already in premalignant precursor lesions, i.e., before the transition to invasive disease, and their distribution is maintained in metastases, and in cell lines derived from primary tumors. These observations are consistent with the interpretation that tumor specific genomic imbalances are drivers of malignant transformation. The mechanisms by which either structural or numerical chromosomal aberrations arise are different. For this Special Issue, we would like to invite manuscripts that aim at elucidating the role of mitotic errors and DNA breakage in tumorigenesis. Furthermore, we would like to explore how aneuploidy affects the global transcriptional equilibrium. We encourage submission of manuscripts that explore mechanisms leading to chromosomal aberrations, including model systems, and manuscripts that discuss diagnostic and therapeutic aspects of specific types of chromosomal changes in cancer. Finally, we would like to also consider the problem of intratumor heterogeneity and its consequences on tumor evolution and therapy response.

Dr. Thomas Ried
Dr. Daniela Hirsch
Dr. Jordi Camps
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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.

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Published Papers (5 papers)

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Research

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19 pages, 1682 KiB  
Article
Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes
by Cheng-Yu Lin, Ankit Shukla, John P. Grady, J. Lynn Fink, Eloise Dray and Pascal H.G. Duijf
Cancers 2018, 10(1), 13; https://doi.org/10.3390/cancers10010013 - 8 Jan 2018
Cited by 15 | Viewed by 6906
Abstract
Chromosomal translocations drive the development of many hematological and some solid cancers. Several factors have been identified to explain the non-random occurrence of translocation breakpoints in the genome. These include chromatin density, gene density and CCCTC-binding factor (CTCF)/cohesin binding site density. However, such [...] Read more.
Chromosomal translocations drive the development of many hematological and some solid cancers. Several factors have been identified to explain the non-random occurrence of translocation breakpoints in the genome. These include chromatin density, gene density and CCCTC-binding factor (CTCF)/cohesin binding site density. However, such factors are at least partially interdependent. Using 13,844 and 1563 karyotypes from human blood and solid cancers, respectively, our multiple regression analysis only identified chromatin density as the primary statistically significant predictor. Specifically, translocation breakpoints preferentially occur in open chromatin. Also, blood and solid tumors show markedly distinct translocation signatures. Strikingly, translocation breakpoints occur significantly more frequently in acrocentric chromosomes than in non-acrocentric chromosomes. Thus, translocations are probably often generated around nucleoli in the inner nucleoplasm, away from the nuclear envelope. Importantly, our findings remain true both in multivariate analyses and after removal of highly recurrent translocations. Finally, we applied pairwise probabilistic co-occurrence modeling. In addition to well-known highly prevalent translocations, such as those resulting in BCR-ABL1 (BCR-ABL) and RUNX1-RUNX1T1 (AML1-ETO) fusion genes, we identified significantly underrepresented translocations with putative fusion genes, which are probably subject to strong negative selection during tumor evolution. Taken together, our findings provide novel insights into the generation and selection of translocations during cancer development. Full article
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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5461 KiB  
Article
Tracking Functional Tumor Cell Subpopulations of Malignant Glioma by Phasor Fluorescence Lifetime Imaging Microscopy of NADH
by Andrew L. Trinh, Hongtao Chen, Yumay Chen, Yuanjie Hu, Zhenzhi Li, Eric R. Siegel, Mark E. Linskey, Ping H. Wang, Michelle A. Digman and Yi-Hong Zhou
Cancers 2017, 9(12), 168; https://doi.org/10.3390/cancers9120168 - 6 Dec 2017
Cited by 27 | Viewed by 6297
Abstract
Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of [...] Read more.
Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment. Full article
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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3619 KiB  
Article
Telomere Shortening in Hematological Malignancies with Tetraploidization—A Mechanism for Chromosomal Instability?
by Eigil Kjeldsen
Cancers 2017, 9(12), 165; https://doi.org/10.3390/cancers9120165 - 30 Nov 2017
Cited by 4 | Viewed by 6370
Abstract
Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise and whether or not they are a cause or a [...] Read more.
Aneuploidy, the presence of an abnormal number of chromosomes in a cell, is one of the most obvious differences between normal and cancer cells. There is, however, debate on how aneuploid cells arise and whether or not they are a cause or a consequence of tumorigenesis. Further, it is important to distinguish aneuploidy (the “state” of the karyotype) from chromosomal instability (CIN; the “rate” of karyotypic change). Although CIN leads to aneuploidy, not all aneuploid cells exhibit CIN. One proposed route to aneuploid cells is through an unstable tetraploid intermediate because tetraploidy promotes chromosomal aberrations and tumorigenesis. Tetraploidy or near-tetraploidy (T/NT) (81–103 chromosomes) karyotypes with or without additional structural abnormalities have been reported in acute leukemia, T-cell and B-cell lymphomas, and solid tumors. In solid tumors it has been shown that tetraploidization can occur in response to loss of telomere protection in the early stages of tumorigenesis in colon cancer, Barrett’s esophagus, and breast and cervical cancers. In hematological malignancies T/NT karyotypes are rare and the role of telomere dysfunction for the induction of tetraploidization is less well characterized. To further our understanding of possible telomere dysfunction as a mechanism for tetrapolydization in hematological cancers we here characterized the chromosomal complement and measured the telomere content by interphase nuclei quantitative fluorescence in situ hybridization (iQFISH) in seven hematological cancer patients with T/NT karyotypes, and after cytogenetic remission. The patients were identified after a search in our local cytogenetic registry in the 5-year period between June 2012 and May 2017 among more than 12,000 analyzed adult patients in this period. One advantage of measuring telomere content by iQFISH is that it is a single-cell analysis so that the telomere content can be distinguished between normal karyotype cells and cells with T/NT karyotypes. We find that the telomeres are particularly short in cells with T/NT karyotypes as compared with normal cells, and in T/NT karyotypes harboring additional chromosomal aberrations as well. These findings suggest that telomere dysfunction in hematological malignancies may be a mechanism for tetraploidization and CIN. Full article
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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Review

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1668 KiB  
Review
The Role of Chromosomal Instability in Cancer and Therapeutic Responses
by Natalia Vargas-Rondón, Victoria E. Villegas and Milena Rondón-Lagos
Cancers 2018, 10(1), 4; https://doi.org/10.3390/cancers10010004 - 28 Dec 2017
Cited by 123 | Viewed by 15288
Abstract
Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four [...] Read more.
Cancer is one of the leading causes of death, and despite increased research in recent years, control of advanced-stage disease and optimal therapeutic responses remain elusive. Recent technological improvements have increased our understanding of human cancer as a heterogeneous disease. For instance, four hallmarks of cancer have recently been included, which in addition to being involved in cancer development, could be involved in therapeutic responses and resistance. One of these hallmarks is chromosome instability (CIN), a source of genetic variation in either altered chromosome number or structure. CIN has become a hot topic in recent years, not only for its implications in cancer diagnostics and prognostics, but also for its role in therapeutic responses. Chromosomal alterations are mainly used to determine genetic heterogeneity in tumors, but CIN could also reveal treatment efficacy, as many therapies are based on increasing CIN, which causes aberrant cells to undergo apoptosis. However, it should be noted that contradictory findings on the implications of CIN for the therapeutic response have been reported, with some studies associating high CIN with a better therapeutic response and others associating it with therapeutic resistance. Considering these observations, it is necessary to increase our understanding of the role CIN plays not only in tumor development, but also in therapeutic responses. This review focuses on recent studies that suggest possible mechanisms and consequences of CIN in different disease types, with a primary focus on cancer outcomes and therapeutic responses. Full article
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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798 KiB  
Review
Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer
by Laura L. Thompson, Lucile M-P. Jeusset, Chloe C. Lepage and Kirk J. McManus
Cancers 2017, 9(11), 151; https://doi.org/10.3390/cancers9110151 - 1 Nov 2017
Cited by 57 | Viewed by 8414
Abstract
Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or [...] Read more.
Cancer is a devastating disease that claims over 8 million lives each year. Understanding the molecular etiology of the disease is critical to identify and develop new therapeutic strategies and targets. Chromosome instability (CIN) is an abnormal phenotype, characterized by progressive numerical and/or structural chromosomal changes, which is observed in virtually all cancer types. CIN generates intratumoral heterogeneity, drives cancer development, and promotes metastatic progression, and thus, it is associated with highly aggressive, drug-resistant tumors and poor patient prognosis. As CIN is observed in both primary and metastatic lesions, innovative strategies that exploit CIN may offer therapeutic benefits and better outcomes for cancer patients. Unfortunately, exploiting CIN remains a significant challenge, as the aberrant mechanisms driving CIN and their causative roles in cancer have yet to be fully elucidated. The development and utilization of CIN-exploiting therapies is further complicated by the associated risks for off-target effects and secondary cancers. Accordingly, this review will assess the strengths and limitations of current CIN-exploiting therapies, and discuss emerging strategies designed to overcome these challenges to improve outcomes and survival for patients diagnosed with cancer. Full article
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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