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Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 40601

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Special Issue Editor

Dr. Kirk J. McManus

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Guest Editor

Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada
Interests: cancer genetics; genome instability; chromosome instability (CIN); aneuploidy; drug target discovery; synthetic lethality; single-cell quantitative imaging microscopy (scQuantIM)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a devastating disease that claims more than 8 million lives throughout the world each year. To improve the lives and outcomes of those living with cancer, greater insight into the aberrant molecular events driving the disease pathogenesis is critical. Chromosome instability (CIN) is a prevalent form of genome instability and an enabling feature of cancer. CIN is defined as an increase in the rate at which whole chromosomes, or large parts thereof, are gained or lost, and is synonymous with cell-to-cell heterogeneity. CIN is proposed to be a key driver of cancer pathogenesis, as it is associated with cellular transformation, intratumoral heterogeneity, metastasis, the acquisition of multi-drug resistance, and poor patient outcomes in a diverse array of cancer types. Remarkably, and despite these associations, the molecular determinants of CIN remain poorly understood.

Currently, many fundamental research groups are employing cutting-edge technologies to identify and characterize the aberrant (CIN) genes and pathways that induce CIN to gain novel insight into disease development and progression. Similarly, many clinical researchers are establishing the utility of these newly discovered CIN genes and CIN as novel biomarkers by correlating their presence/absence with health outcomes, treatment response, and disease recurrence. Accordingly, fundamental, applied, and clinical research areas are now strategically positioned to gain unprecedented insight into the relationships between CIN, cancer pathogenesis, and health outcomes.

CIN is also being explored in numerous therapeutic contexts, which include exacerbating CIN to induce catastrophic genetic events leading to tumor cell killing, limiting CIN to prevent tumor evolution and drug resistance mechanisms, or targeting the underlying aberrant genetic events (i.e., CIN genes) through synthetic lethal paradigms. Thus, as our understanding of the molecular determinants driving CIN continues to expand, these strategies may hold tremendous clinical value in the near future. This Special Issue will highlight the impact CIN has in cancer pathogenesis, patient outcomes and treatment strategies, by providing the current status of fundamental, applied, and clinical research on CIN.

Dr. Kirk J. McManus
Guest Editor

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.

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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.

Keywords

cancer
genome instability
chromosome instability (CIN)
aneuploidy
cancer pathogenesis
health outcomes
therapeutic strategies
synthetic lethality

Published Papers (10 papers)

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Research

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15 pages, 16088 KiB

Open AccessArticle

DNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients

by Ioan T. Bold, Ann-Kathrin Specht, Conrad F. Droste, Alexandra Zielinski, Felix Meyer, Till S. Clauditz, Adrian Münscher, Stefan Werner, Kai Rothkamm, Cordula Petersen and Kerstin Borgmann

Cancers 2021, 13(6), 1194; https://doi.org/10.3390/cancers13061194 - 10 Mar 2021

Cited by 8 | Viewed by 2680

Abstract

Aneuploidy is a consequence of chromosomal instability (CIN) that affects prognosis. Gene expression levels associated with aneuploidy provide insight into the molecular mechanisms underlying CIN. Based on the gene signature whose expression was consistent with functional aneuploidy, the CIN70 score was established. We observed an association of CIN70 score and survival in 519 HNSCC patients in the TCGA dataset; the 15% patients with the lowest CIN70 score showed better survival (p = 0.11), but association was statistically non-significant. This correlated with the expression of 39 proteins of the major repair complexes. A positive association with survival was observed for MSH2, XRCC1, MRE11A, BRCA1, BRCA2, LIG1, DNA2, POLD1, MCM2, RAD54B, claspin, a negative for ERCC1, all related with replication. We hypothesized that expression of these factors leads to protection of replication through efficient repair and determines survival and resistance to therapy. Protein expression differences in HNSCC cell lines did not correlate with cellular sensitivity after treatment. Rather, it was observed that the stability of the DNA replication fork determined resistance, which was dependent on the ATR/CHK1-mediated S-phase signaling cascade. This suggests that it is not the expression of individual DNA repair proteins that causes therapy resistance, but rather a balanced expression and coordinated activation of corresponding signaling cascades. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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23 pages, 5225 KiB

Open AccessArticle

Reduced USP22 Expression Impairs Mitotic Removal of H2B Monoubiquitination, Alters Chromatin Compaction and Induces Chromosome Instability That May Promote Oncogenesis

by Lucile M. Jeusset, Brent J. Guppy, Zelda Lichtensztejn, Darin McDonald and Kirk J. McManus

Cancers 2021, 13(5), 1043; https://doi.org/10.3390/cancers13051043 - 2 Mar 2021

Cited by 8 | Viewed by 2369

Abstract

Chromosome instability (CIN) is an enabling feature of oncogenesis associated with poor patient outcomes, whose genetic determinants remain largely unknown. As mitotic chromatin compaction defects can compromise the accuracy of chromosome segregation into daughter cells and drive CIN, characterizing the molecular mechanisms ensuring accurate chromatin compaction may identify novel CIN genes. In vitro, histone H2B monoubiquitination at lysine 120 (H2Bub1) impairs chromatin compaction, while in vivo H2Bub1 is rapidly depleted from chromatin upon entry into mitosis, suggesting that H2Bub1 removal may be a pre-requisite for mitotic fidelity. The deubiquitinating enzyme USP22 catalyzes H2Bub1 removal in interphase and may also be required for H2Bub1 removal in early mitosis to maintain chromosome stability. In this study, we demonstrate that siRNA-mediated USP22 depletion increases H2Bub1 levels in early mitosis and induces CIN phenotypes associated with mitotic chromatin compaction defects revealed by super-resolution microscopy. Moreover, USP22-knockout models exhibit continuously changing chromosome complements over time. These data identify mitotic removal of H2Bub1 as a critical determinant of chromatin compaction and faithful chromosome segregation. We further demonstrate that USP22 is a CIN gene, indicating that USP22 deletions, which are frequent in many tumor types, may drive genetic heterogeneity and contribute to cancer pathogenesis. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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14 pages, 2143 KiB

Open AccessArticle

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

by Johanna Rieckhoff, Felix Meyer, Sandra Classen, Alexandra Zielinski, Britta Riepen, Harriet Wikman, Cordula Petersen, Kai Rothkamm, Kerstin Borgmann and Ann Christin Parplys

Cancers 2020, 12(10), 2809; https://doi.org/10.3390/cancers12102809 - 29 Sep 2020

Cited by 7 | Viewed by 2743

Abstract

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. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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19 pages, 5876 KiB

Open AccessArticle

Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer

by Christine Lee, Kristine J. Fernandez, Sarah Alexandrou, C. Marcelo Sergio, Niantao Deng, Samuel Rogers, Andrew Burgess and C. Elizabeth Caldon

Cancers 2020, 12(8), 2268; https://doi.org/10.3390/cancers12082268 - 13 Aug 2020

Cited by 16 | Viewed by 4079

Abstract

Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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15 pages, 2194 KiB

Open AccessArticle

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

by Claudia Galofré, Öykü Gönül Geyik, Elena Asensio, Darawalee Wangsa, Daniela Hirsch, Carolina Parra, Jordi Saez, Meritxell Mollà, Zeynep Yüce, Antoni Castells, Thomas Ried and Jordi Camps

Cancers 2020, 12(5), 1118; https://doi.org/10.3390/cancers12051118 - 30 Apr 2020

Cited by 12 | Viewed by 5316

Abstract

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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17 pages, 2870 KiB

Open AccessArticle

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

by Laura L. Thompson, Allison K. Baergen, Zelda Lichtensztejn and Kirk J. McManus

Cancers 2020, 12(3), 531; https://doi.org/10.3390/cancers12030531 - 25 Feb 2020

Cited by 21 | Viewed by 3058

Abstract

Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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Review

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23 pages, 1311 KiB

Open AccessReview

Chromosomal Instability in Acute Myeloid Leukemia

by Mateus de Oliveira Lisboa, Paulo Roberto Slud Brofman, Ana Teresa Schmid-Braz, Aline Rangel-Pozzo and Sabine Mai

Cancers 2021, 13(11), 2655; https://doi.org/10.3390/cancers13112655 - 28 May 2021

Cited by 14 | Viewed by 4236

Abstract

Chromosomal instability (CIN), the increasing rate in which cells acquire new chromosomal alterations, is one of the hallmarks of cancer. Many studies highlighted CIN as an important mechanism in the origin, progression, and relapse of acute myeloid leukemia (AML). The ambivalent feature of CIN as a cancer-promoting or cancer-suppressing mechanism might explain the prognostic variability. The latter, however, is described in very few studies. This review highlights the important CIN mechanisms in AML, showing that CIN signatures can occur largely in all the three major AML types (de novo AML, secondary-AML, and therapy-related-AML). CIN features in AML could also be age-related and reflect the heterogeneity of the disease. Although most of these abnormalities show an adverse prognostic value, they also offer a strong new perspective on personalized therapy approaches, which goes beyond assessing CIN in vitro in patient tumor samples to predict prognosis. Current and emerging AML therapies are exploring CIN to improve AML treatment, which includes blocking CIN or increasing CIN beyond the limit threshold to induce cell death. We argue that the characterization of CIN features, not included yet in the routine diagnostic of AML patients, might provide a better stratification of patients and be extended to a more personalized therapeutic approach. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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22 pages, 1120 KiB

Open AccessReview

Genomic Instability in Circulating Tumor Cells

by Monique Oliveira Freitas, John Gartner, Aline Rangel-Pozzo and Sabine Mai

Cancers 2020, 12(10), 3001; https://doi.org/10.3390/cancers12103001 - 16 Oct 2020

Cited by 8 | Viewed by 3329

Abstract

Circulating tumor cells (CTCs) can promote distant metastases and can be obtained through minimally invasive liquid biopsy for clinical assessment in cancer patients. Having both genomic heterogeneity and instability as common features, the genetic characterization of CTCs can serve as a powerful tool for a better understanding of the molecular changes occurring at tumor initiation and during tumor progression/metastasis. In this review, we will highlight recent advances in the detection and quantification of tumor cell heterogeneity and genomic instability in CTCs. We will focus on the contribution of chromosome instability studies to genetic heterogeneity in CTCs at the single-CTC level by discussing data from different cancer subtypes and their impact on diagnosis and precision medicine. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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26 pages, 619 KiB

Open AccessReview

The CINs of Polo-Like Kinase 1 in Cancer

by Chelsea E. Cunningham, Mackenzie J. MacAuley, Frederick S. Vizeacoumar, Omar Abuhussein, Andrew Freywald and Franco J. Vizeacoumar

Cancers 2020, 12(10), 2953; https://doi.org/10.3390/cancers12102953 - 13 Oct 2020

Cited by 16 | Viewed by 3862

Abstract

Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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Graphical abstract

19 pages, 1235 KiB

Open AccessReview

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

by Raghvendra Vishwakarma and Kirk J. McManus

Cancers 2020, 12(4), 824; https://doi.org/10.3390/cancers12040824 - 29 Mar 2020

Cited by 39 | Viewed by 7211

Abstract

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. Full article

(This article belongs to the Special Issue Chromosome Instability – Implications in Disease Pathogenesis, Health Outcomes and Therapeutic Targeting)

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