Causes and Consequences of Chromosomal Instability in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 19522

Special Issue Editor

Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Interests: chromosomal instability; chromosome segregation; kinetochore–microtubule attachment; spindle assembly checkpoint; genomic instability; cancer heterogeneity

Special Issue Information

Dear Colleagues,

This Special Issue will highlight recent advances in our understanding of chromosomal instability (CIN), a common feature of cancer. CIN is a condition in which chromosome mis-segregation occurs at a high rate that gives rise to aneuploid cells and is related to poor prognosis, drug resistance, and metastasis. 

Recent studies have revealed various mechanisms that cause chromosomal instability by disrupting machinery to ensure faithful transmission of genetic information. Although aneuploidy is generally disadvantageous to cellular fitness, genomic heterogeneity resulting from CIN supposedly facilitates the selection of cells that acquire a growth advantage. Expanding information on the cancer genome is unveiling how chromosomal instability contributes to cancer initiation and progression and how clonal selection occurs. Importantly, CIN and aneuploidy are now emerging as targets for cancer therapy as an Achilles’ heel of cancer. 

This Special Issue encompasses research articles, experts’ communications, and timely review articles covering a wide range of topics related to chromosomal instability in cancer.

Prof. Dr. Kozo Tanaka
Guest Editor

Manuscript Submission Information

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Keywords

  • chromosomal instability
  • aneuploidy
  • cancer heterogeneity
  • chromosome segregation
  • mitosis
  • therapeutic resistance
  • tumor progression

Published Papers (6 papers)

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Research

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21 pages, 2977 KiB  
Article
Congenital Aneuploidy in Klinefelter Syndrome with B-Cell Acute Lymphoblastic Leukemia Might Be Associated with Chromosomal Instability and Reduced Telomere Length
by Eigil Kjeldsen
Cancers 2022, 14(9), 2316; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092316 - 06 May 2022
Cited by 3 | Viewed by 2226
Abstract
Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a “vicious cycle” [...] Read more.
Rare congenital aneuploid conditions such as trisomy 13, trisomy 18, trisomy 21 and Klinefelter syndrome (KS, 47,XXY) are associated with higher susceptibility to developing cancer compared with euploid genomes. Aneuploidy frequently co-exists with chromosomal instability, which can be viewed as a “vicious cycle” where aneuploidy potentiates chromosomal instability, leading to further karyotype diversity, and in turn, paving the adaptive evolution of cancer. However, the relationship between congenital aneuploidy per se and tumor initiation and/or progression is not well understood. We used G-banding analysis, array comparative genomic hybridization analysis and quantitative fluorescence in situ hybridization for telomere length analysis to characterize the leukemic blasts of a three-year-old boy with KS and B-cell acute lymphoblastic leukemia (B-ALL), to gain insight into genomic evolution mechanisms in congenital aneuploidy and leukemic development. We found chromosomal instability and a significant reduction in telomere length in leukemic blasts when compared with the non-leukemic aneuploid cells. Reviewing published cases with KS and B-ALL revealed 20 additional cases with B-ALL diagnostic cytogenetics. Including our present case, 67.7% (14/21) had acquired two or more additional chromosomal aberrations at B-ALL diagnosis. The presented data indicate that congenital aneuploidy in B-ALL might be associated with chromosomal instability, which may be fueled by enhanced telomere attrition. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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19 pages, 5760 KiB  
Article
Mad2 Induced Aneuploidy Contributes to Eml4-Alk Driven Lung Cancer by Generating an Immunosuppressive Environment
by Kristina Alikhanyan, Yuanyuan Chen, Kalman Somogyi, Simone Kraut and Rocio Sotillo
Cancers 2021, 13(23), 6027; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236027 - 30 Nov 2021
Cited by 2 | Viewed by 2004
Abstract
Aneuploidy, an imbalance number of chromosomes, is frequently observed in lung cancer and inversely correlates with patient survival. Paradoxically, an aneuploid karyotype has detrimental consequences on cellular fitness, and it has been proposed that aneuploid cells, at least in vitro, generate signals for [...] Read more.
Aneuploidy, an imbalance number of chromosomes, is frequently observed in lung cancer and inversely correlates with patient survival. Paradoxically, an aneuploid karyotype has detrimental consequences on cellular fitness, and it has been proposed that aneuploid cells, at least in vitro, generate signals for their own elimination by NK cells. However, how aneuploidy affects tumor progression as well as the interplay between aneuploid tumor cells and the tumor microenvironment is still unclear. We generated a new mouse model in which overexpression of Mad2 was almost entirely restricted to normal epithelial cells of the lung, and combined it with an oncogenic Eml4-Alk chromosome inversion. This combination resulted in a higher tumor burden and an increased number of tumor nodules compared to control Eml4-Alk mice alone. The FISH analysis detected significant differences in the aneuploidy levels in the non-tumor regions of Eml4-Alk+Mad2 compared to Eml4-Alk alone, although both tumor groups presented similar levels of aneuploidy. We further show that aneuploid cells in the non-tumor areas adjacent to lung tumors recruit immune cells, such as tumor-associated macrophages. In fact, these areas presented an increase in alveolar macrophages, neutrophils, decreased cytotoxic CD8+ T cells, and IFN-γ, suggesting that aneuploid cells in the surrounding tumor areas create an immunosuppressive signature that might contribute to lung tumor initiation and progression. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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Review

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17 pages, 982 KiB  
Review
Chromosomal Instability, Selection and Competition: Factors That Shape the Level of Karyotype Intra-Tumor Heterogeneity
by Tom van den Bosch, Sarah Derks and Daniël M. Miedema
Cancers 2022, 14(20), 4986; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14204986 - 12 Oct 2022
Cited by 7 | Viewed by 2453
Abstract
Intra-tumor heterogeneity (ITH) is a pan-cancer predictor of survival, with high ITH being correlated to a dismal prognosis. The level of ITH is, hence, a clinically relevant characteristic of a malignancy. ITH of karyotypes is driven by chromosomal instability (CIN). However, not all [...] Read more.
Intra-tumor heterogeneity (ITH) is a pan-cancer predictor of survival, with high ITH being correlated to a dismal prognosis. The level of ITH is, hence, a clinically relevant characteristic of a malignancy. ITH of karyotypes is driven by chromosomal instability (CIN). However, not all new karyotypes generated by CIN are viable or competitive, which limits the amount of ITH. Here, we review the cellular processes and ecological properties that determine karyotype ITH. We propose a framework to understand karyotype ITH, in which cells with new karyotypes emerge through CIN, are selected by cell intrinsic and cell extrinsic selective pressures, and propagate through a cancer in competition with other malignant cells. We further discuss how CIN modulates the cell phenotype and immune microenvironment, and the implications this has for the subsequent selection of karyotypes. Together, we aim to provide a comprehensive overview of the biological processes that shape the level of karyotype heterogeneity. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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12 pages, 1129 KiB  
Review
Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects
by Jayastu Senapati and Koji Sasaki
Cancers 2022, 14(10), 2533; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102533 - 21 May 2022
Cited by 6 | Viewed by 3698
Abstract
The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome [...] Read more.
The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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29 pages, 3203 KiB  
Review
Keep Calm and Carry on with Extra Centrosomes
by Batuhan Mert Kalkan, Selahattin Can Ozcan, Nicholas J. Quintyne, Samantha L. Reed and Ceyda Acilan
Cancers 2022, 14(2), 442; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020442 - 17 Jan 2022
Cited by 8 | Viewed by 4724
Abstract
Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of [...] Read more.
Aberrations in the centrosome number and structure can readily be detected at all stages of tumor progression and are considered hallmarks of cancer. Centrosome anomalies are closely linked to chromosome instability and, therefore, are proposed to be one of the driving events of tumor formation and progression. This concept, first posited by Boveri over 100 years ago, has been an area of interest to cancer researchers. We have now begun to understand the processes by which these numerical and structural anomalies may lead to cancer, and vice-versa: how key events that occur during carcinogenesis could lead to amplification of centrosomes. Despite the proliferative advantages that having extra centrosomes may confer, their presence can also lead to loss of essential genetic material as a result of segregational errors and cancer cells must deal with these deadly consequences. Here, we review recent advances in the current literature describing the mechanisms by which cancer cells amplify their centrosomes and the methods they employ to tolerate the presence of these anomalies, focusing particularly on centrosomal clustering. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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22 pages, 3063 KiB  
Review
Attenuated Chromosome Oscillation as a Cause of Chromosomal Instability in Cancer Cells
by Kenji Iemura, Yujiro Yoshizaki, Kinue Kuniyasu and Kozo Tanaka
Cancers 2021, 13(18), 4531; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184531 - 09 Sep 2021
Cited by 3 | Viewed by 3282
Abstract
Chromosomal instability (CIN) is commonly seen in cancer cells, and related to tumor progression and poor prognosis. Among the causes of CIN, insufficient correction of erroneous kinetochore (KT)-microtubule (MT) attachments plays pivotal roles in various situations. In this review, we focused on the [...] Read more.
Chromosomal instability (CIN) is commonly seen in cancer cells, and related to tumor progression and poor prognosis. Among the causes of CIN, insufficient correction of erroneous kinetochore (KT)-microtubule (MT) attachments plays pivotal roles in various situations. In this review, we focused on the previously unappreciated role of chromosome oscillation in the correction of erroneous KT-MT attachments, and its relevance to the etiology of CIN. First, we provided an overview of the error correction mechanisms for KT-MT attachments, especially the role of Aurora kinases in error correction by phosphorylating Hec1, which connects MT to KT. Next, we explained chromosome oscillation and its underlying mechanisms. Then we introduced how chromosome oscillation is involved in the error correction of KT-MT attachments, based on recent findings. Chromosome oscillation has been shown to promote Hec1 phosphorylation by Aurora A which localizes to the spindle. Finally, we discussed the link between attenuated chromosome oscillation and CIN in cancer cells. This link underscores the role of chromosome dynamics in mitotic fidelity, and the mutual relationship between defective chromosome dynamics and CIN in cancer cells that can be a target for cancer therapy. Full article
(This article belongs to the Special Issue Causes and Consequences of Chromosomal Instability in Cancer)
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