Genes

Research

16 pages, 4511 KiB

Open AccessArticle

Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes

by Ninel M. Vainshelbaum, Pawel Zayakin, Regina Kleina, Alessandro Giuliani and Jekaterina Erenpreisa

Genes 2019, 10(8), 613; https://doi.org/10.3390/genes10080613 - 13 Aug 2019

Cited by 11 | Viewed by 4895

Abstract

Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) [...] Read more.

Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumor types, and was especially high in seminoma. For all tumor types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state (r ≈ 0.9, p < 0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in three of the five benign tumor types, especially notable in colon adenoma. Principal component analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumor types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome (a possible mimic of the fertilization aberration, 69, XXY digyny) associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results as a secondary factor from chromosome instability. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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22 pages, 4572 KiB

Open AccessArticle

The Cancer Aneuploidy Paradox: In the Light of Evolution

by Kristine Salmina, Anda Huna, Martins Kalejs, Dace Pjanova, Harry Scherthan, Mark S. Cragg and Jekaterina Erenpreisa

Genes 2019, 10(2), 83; https://doi.org/10.3390/genes10020083 - 25 Jan 2019

Cited by 46 | Viewed by 7396

Abstract

Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform the segregation of two parental groups of end-to-end linked [...] Read more.

Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform the segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and a homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or by radial cytotomy including pedogamic exchanges) and by the release of secondary cells and/or the formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle checkpoint. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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Review

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31 pages, 1183 KiB

Open AccessReview

Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

by Nicolaas C. Baudoin and Mathew Bloomfield

Genes 2021, 12(4), 558; https://doi.org/10.3390/genes12040558 - 12 Apr 2021

Cited by 15 | Viewed by 5703

Abstract

Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally [...] Read more.

Cancer is a disease of cellular evolution. For this cellular evolution to take place, a population of cells must contain functional heterogeneity and an assessment of this heterogeneity in the form of natural selection. Cancer cells from advanced malignancies are genomically and functionally very different compared to the healthy cells from which they evolved. Genomic alterations include aneuploidy (numerical and structural changes in chromosome content) and polyploidy (e.g., whole genome doubling), which can have considerable effects on cell physiology and phenotype. Likewise, conditions in the tumor microenvironment are spatially heterogeneous and vastly different than in healthy tissues, resulting in a number of environmental niches that play important roles in driving the evolution of tumor cells. While a number of studies have documented abnormal conditions of the tumor microenvironment and the cellular consequences of aneuploidy and polyploidy, a thorough overview of the interplay between karyotypically abnormal cells and the tissue and tumor microenvironments is not available. Here, we examine the evidence for how this interaction may unfold during tumor evolution. We describe a bidirectional interplay in which aneuploid and polyploid cells alter and shape the microenvironment in which they and their progeny reside; in turn, this microenvironment modulates the rate of genesis for new karyotype aberrations and selects for cells that are most fit under a given condition. We conclude by discussing the importance of this interaction for tumor evolution and the possibility of leveraging our understanding of this interplay for cancer therapy. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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19 pages, 4231 KiB

Open AccessReview

Illegitimate and Repeated Genomic Integration of Cell-Free Chromatin in the Aetiology of Somatic Mosaicism, Ageing, Chronic Diseases and Cancer

by Gorantla V. Raghuram, Shahid Chaudhary, Shweta Johari and Indraneel Mittra

Genes 2019, 10(6), 407; https://doi.org/10.3390/genes10060407 - 28 May 2019

Cited by 16 | Viewed by 7594

Abstract

Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal [...] Read more.

Emerging evidence suggests that an individual is a complex mosaic of genetically divergent cells. Post-zygotic genomes of the same individual can differ from one another in the form of single nucleotide variations, copy number variations, insertions, deletions, inversions, translocations, other structural and chromosomal variations and footprints of transposable elements. High-throughput sequencing has led to increasing detection of mosaicism in healthy individuals which is related to ageing, neuro-degenerative disorders, diabetes mellitus, cardiovascular diseases and cancer. These age-related disorders are also known to be associated with significant increase in DNA damage and inflammation. Herein, we discuss a newly described phenomenon wherein the genome is under constant assault by illegitimate integration of cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body every day. We propose that such repeated genomic integration of cfCh followed by dsDNA breaks and repair by non-homologous-end-joining as well as physical damage to chromosomes occurring throughout life may lead to somatic/chromosomal mosaicism which would increase with age. We also discuss the recent finding that genomic integration of cfCh and the accompanying DNA damage is associated with marked activation of inflammatory cytokines. Thus, the triple pathologies of somatic mosaicism, DNA/chromosomal damage and inflammation brought about by a common mechanism of genomic integration of cfCh may help to provide an unifying model for the understanding of aetiologies of the inter-related conditions of ageing, degenerative disorders and cancer. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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25 pages, 1854 KiB

Open AccessReview

Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism

by Ivan Y. Iourov, Svetlana G. Vorsanova, Yuri B. Yurov and Sergei I. Kutsev

Genes 2019, 10(5), 379; https://doi.org/10.3390/genes10050379 - 19 May 2019

Cited by 47 | Viewed by 6097

Abstract

Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout [...] Read more.

Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout the ontogeny, chromosomal mosaicism may mediate genome/chromosome instability and intercellular diversity in health and disease in a bottleneck fashion. However, the ubiquity of negligibly small populations of cells with abnormal karyotypes results in difficulties of the interpretation and detection, which may be nonetheless solved by post-genomic cytogenomic technologies. In the post-genomic era, it has become possible to uncover molecular and cellular pathways to genome/chromosome instability (chromosomal mosaicism or heterogeneity) using advanced whole-genome scanning technologies and bioinformatic tools. Furthermore, the opportunities to determine the effect of chromosomal abnormalities on the cellular phenotype seem to be useful for uncovering the intrinsic consequences of chromosomal mosaicism. Accordingly, a post-genomic review of chromosomal mosaicism in the ontogenetic and pathogenetic contexts appears to be required. Here, we review chromosomal mosaicism in its widest sense and discuss further directions of cyto(post)genomic research dedicated to chromosomal heterogeneity. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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22 pages, 2229 KiB

Open AccessReview

Nonclonal Chromosome Aberrations and Genome Chaos in Somatic and Germ Cells from Patients and Survivors of Hodgkin Lymphoma

by Sara Frias, Sandra Ramos, Consuelo Salas, Bertha Molina, Silvia Sánchez and Roberto Rivera-Luna

Genes 2019, 10(1), 37; https://doi.org/10.3390/genes10010037 - 10 Jan 2019

Cited by 23 | Viewed by 5084

Abstract

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both [...] Read more.

Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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Other

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20 pages, 2713 KiB

Open AccessConcept Paper

When Three Isn’t a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers

by Kristine Salmina, Bogdan I. Gerashchenko, Michael Hausmann, Ninel M. Vainshelbaum, Pawel Zayakin, Juris Erenpreiss, Talivaldis Freivalds, Mark S. Cragg and Jekaterina Erenpreisa

Genes 2019, 10(7), 551; https://doi.org/10.3390/genes10070551 - 19 Jul 2019

Cited by 14 | Viewed by 5945

Abstract

Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a [...] Read more.

Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a conceptual framework of the digyny-like origin of this karyotype based on the germline features of malignant tumors and adaptive capacity of digyny, which supports survival in adverse conditions. Studying how the recombinatorial reproduction via diploidy can be executed in primary cancer samples and HeLa cells after DNA damage, we report the first evidence that diploid and triploid cell sub-populations constitutively coexist and inter-change genomes via endoreduplicated polyploid cells generated through genotoxic challenge. We show that irradiated triploid HeLa cells can enter tripolar mitosis producing three diploid sub-subnuclei by segregation and pairwise fusions of whole genomes. Considering the upregulation of meiotic genes in tumors, we propose that the reconstructed diploid sub-cells can initiate pseudo-meiosis producing two “gametes” (diploid “maternal” and haploid “paternal”) followed by digynic-like reconstitution of a triploid stemline that returns to mitotic cycling. This process ensures tumor survival and growth by (1) DNA repair and genetic variation, (2) protection against recessive lethal mutations using the third genome. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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21 pages, 1179 KiB

Open AccessPerspective

Micronuclei and Genome Chaos: Changing the System Inheritance

by Christine J. Ye, Zachary Sharpe, Sarah Alemara, Stephanie Mackenzie, Guo Liu, Batoul Abdallah, Steve Horne, Sarah Regan and Henry H. Heng

Genes 2019, 10(5), 366; https://doi.org/10.3390/genes10050366 - 13 May 2019

Cited by 98 | Viewed by 9394

Abstract

Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which [...] Read more.

Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identified. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos. However, the newly revealed complexity also causes confusion regarding the common mechanisms of micronuclei and their impact on genomic systems. To make sense of these diverse and even conflicting observations, the genome theory is applied in order to explain a stress mediated common mechanism of the generation of micronuclei and their contribution to somatic evolution by altering the original set of information and system inheritance in which cellular selection functions. To achieve this goal, a history and a current new trend of micronuclei research is briefly reviewed, followed by a review of arising key issues essential in advancing the field, including the re-classification of micronuclei and how to unify diverse molecular characterizations. The mechanistic understanding of micronuclei and their biological function is re-examined based on the genome theory. Specifically, such analyses propose that micronuclei represent an effective way in changing the system inheritance by altering the coding of chromosomes, which belongs to the common evolutionary mechanism of cellular adaptation and its trade-off. Further studies of the role of micronuclei in disease need to be focused on the behavior of the adaptive system rather than specific molecular mechanisms that generate micronuclei. This new model can clarify issues important to stress induced micronuclei and genome instability, the formation and maintenance of genomic information, and cellular evolution essential in many common and complex diseases such as cancer. Full article

(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)

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