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Event: 1896

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Genomic instability

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Genomic instability
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
chromosomal instability chromosome increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Frustrated phagocytosis leads to malignant mesothelioma KeyEvent Penny Nymark (send email) Under development: Not open for comment. Do not cite
Activation of uterine estrogen receptor-alfa, endometrial adenocarcinoma KeyEvent Barbara Viviani (send email) Under development: Not open for comment. Do not cite Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Female

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Genomic instability is a condition that can lead to cancer development (Hanahan & Weinberg, 2011) and is referred to the fact that cancer cells are defective in the quality of DNA replication and the subsequent DNA partition to daughter cells during cell division. This may occur at the level of single nucleotides (leading to point mutations) or in entire chromosome (leading to chromosome aberrations and anomalies in the karyotype) (Lengauer et al., 1998; Sieber et al., 2005; Negrini et al., 2010). The preservation of the genomic stability is fundamental for cellular integrity to prevent errors from DNA replication or exposure to endogenous or exogenous genotoxins (Yao & Dai, 2014).

The genomic integrity is monitored by several surveillance mechanisms: DNA damage checkpoint, DNA repair machinery and mitotic checkpoint; a defect in the regulation of one of these mechanisms can lead to genomic instability, which may facilitate cells malignant transformation (Yao & Dai, 2014).

DNA damage checkpoint: p53 (tumor protein P53, the name derives from its apparent molecular mass) is a tumor suppressor gene that has an important role in DNA repair, cellular senescence, apoptosis and regulates cell cycle progression. It is the most frequently mutated gene in human cancers: p53 loss of function mutations are found in more than 50% of cancers (Ellenson et al., 2015; Baugh et al., 2018). P53 recognizes different forms of cellular stress, principally DNA damage, and, in response to them, p53 blocks cell proliferation, arresting cell cycle in phase G1 to inhibit the propagation of DNA damage (Levine, 1997; Brown et al., 2007; Ellenson et al., 2015]. P53 can also induce apoptosis (programmed cell death) or senescence when the damage is too severe, to avoid the possible malignant transformation (Efeyan et al., 2006; Zhang et al., 2011). P53 also responds to oncogenic stress: this occurs through the upstream p19ARF (alternative reading frame tumor suppressor) and MDM2 (mouse double minute 2 homolog) pathway. ARF is induced by elevated proliferation signals caused, for example, by the overexpression of MYC and oncogenic RAS. ARF then antagonizes MDM2 activity to block p53 function, leading to cell cycle arrest or apoptosis (Palmero et al., 1998; Zindy et al., 1998).

DNA Repair Pathway: there are different repair pathways, such as the nucleotide excision repair (NER) and the mismatch repair system (MMR). NER acts through several steps: recognition of the lesion site, incision of the damaged DNA strand, DNA synthesis and link of the uncouple flanks by ligase enzymes. Each component of the NER pathway is fundamental in the correct repair of the damaged sites (Mitchell et al., 2003). The mismatch repair system corrects the base-base mismatches caused by insertion/deletions or replication errors (Kunkel & Erie, 2005).

Mitotic Checkpoint: its function is to control the correct attachment of the spindle microtubules to all condensed chromosomes before the nuclear division during mitosis (Yao & Dai, 2014). There are multiple components that mediate the mitotic checkpoint functions during mitosis. For example, Aurora B is responsible for the phosphorylation of histone H3 serine 10 (H3S10) during mitosis (Carmena & Earnshaw, 2003): it is thought that this mechanism plays a role in super-condensation and super compaction of chromosomes during mitosis. Another protein involved is the Protein phosphatase 2A (PP2A), a serine/threonine phosphatase that dephosphorylates different substrates (Shi, 2009) and has an essential role for the maintenance of centromeric cohesion of sister chromatids before the entry in anaphase (Riedel et al., 2006; Tang et al., 2006).

Genomic instability is principally characterized by:

Microsatellite instability (MSI): microsatellites are short repetitive DNA sequences that are distributed in the entire genome. When there are DNA replication errors, these are repaired by nuclear enzymes of the DNA mismatch repair system. When one of the repair enzymes is not functioning, some replication errors are not corrected; these events may accumulate and facilitate tumor development (Esteller et al., 1999; Kanaya et al., 2005). MSI is caused by the accumulation of insertions and/or deletions in short DNA repeats or microsatellites leading to different lengths of repeat. The accumulation of these mutations affects genes with important regulatory functions, for example tumor suppressor genes (Tashiro & Katabuchi, 2014).

Chromosome instability: it consists of an increased rate of chromosomal incorrect aggregation during mitosis, resulting in an incorrect chromosome number and/or in an abnormal chromosome structure (Rao et al., 2009). Failure of the correct chromosome segregation leads to cell death or to malignant transformation (Yao & Dai, 2014). Genes that, when altered, may lead to chromosome instability include genes involved in chromosome condensation, sister-chromatid cohesion, function and centrosome/ microtubule formation and dynamics (Murray, 1995; Elledge, 1996; Paulovich et al., 1997).

Increased frequencies of base pair mutation: it has been found in hereditary cancers that the loss of function of DNA repair genes may cause increased frequency of base pair mutation. This event and MSI in hereditary DNA damage repair gene cases have indicated that the loss of genetic integrity maintenance may be a cause of genomic instability and the initiation of cancer: it has been proposed that the increased mutations in genes involved in the maintenance of genetic stability may be an early step in tumor progression (Yao & Dai, 2014).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Genomic instability

There are several methods to detect genetic instability in cancers: to assess instability is important to repeat measurements in the cell populations throughout the tumor development. For example:

The analysis of the karyotype of a single cell permits the identification of chromosome number abnormalities, called aneuploidy, and the identification of rearrangements in the entire genome, such as inversions and translocations (Beheshti et al., 2001; Wan & Ma, 2012). Fluorescence in situ hybridization (FISH), referred to as spectral karyotyping (SKY), is a method that has facilitated the assessment of chromosomal instability: this technique stains each chromosome with different colored fluorophore readily enabling the presence of rearrangements or modifications in chromosomes (Bayani & Squire, 2001; Wan & Ma., 2012).

PCR (polymerase chain reaction) is a multicellular approach, used to detect MSI: it amplifies known microsatellite regions, and the lengths of the PCR products (short tandem repeats) are compared in the tumoral and normal DNA to determine the state of MSI (Janavicius et al., 2010; Meyerson et al., 2010; Vilar & Gruber, 2010).

Flow cytometry is another multicellular approach that, through the measurement of cells in suspension while they are passing through a laser beam, scatter light and emit fluorescence, estimates cell ploidy measuring DNA content (that is proportional to the intensity of the fluorescence) and the stage of the cells in cell cycle. The subsequent comparison between the estimated ploidy in the G0/G1 normal and malignant cell may estimate genomic instability in cancer cells (D’Urso et al., 2010; Darzynkiewicz et al., 2017).

Accumulation of mutations

OECD (2016a) Organisation for economic co-operation and development. Test guideline 476: in vitro mammalian cell gene mutation tests using the hprt and xprt gene.

OECD (2016b) Organisation for economic co-operation and development. Test guideline 490: in vitro mammalian cell gene mutation tests using the thymidine kinase gene.

In vitro cell transformation

OECD (2016e) Organisation for economic co-operation and development. Guidance document 231 on the in vitro BHAS 42 Cell Transformation Assay.

This GD provides an in vitro procedure using the Bhas 42 CTA, which can be used for hazard identification of potential carcinogenicity of chemicals with initiating and/or promoting activity. The test method described is based upon the protocols of previous reports and that published by the EURL ECVAM.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Genetic errors that increase mutation rates are quite common in cancers: they accelerate the acquisition of several mutations that are necessary for the transformation and subsequent tumor progression (Ellenson et al., 2015).

References

List of the literature that was cited for this KE description. More help

Baugh, E. H., Ke, H., Levine, A. J., Bonneau, R. A., & Chan, C. S. (2018). Why are there hotspot mutations in the TP53 gene in human cancers?. Cell death and differentiation, 25(1), 154–160. https://doi.org/10.1038/cdd.2017.180

Brown, L., Boswell, S., Raj, L., & Lee, S. W. (2007). Transcriptional targets of p53 that regulate cellular proliferation. Critical reviews in eukaryotic gene expression, 17(1), 73–85. https://doi.org/10.1615/critreveukargeneexpr.v17.i1.50

Carmena, M., & Earnshaw, W. C. (2003). The cellular geography of aurora kinases. Nature reviews. Molecular cell biology, 4(11), 842–854. https://doi.org/10.1038/nrm1245

Darzynkiewicz, Z., Huang, X., & Zhao, H. (2017). Analysis of Cellular DNA Content by Flow Cytometry. Current protocols in cytometry, 82, 7.5.1–7.5.20. https://doi.org/10.1002/cpcy.28

D'Urso, V., Collodoro, A., Mattioli, E., Giordano, A., & Bagella, L. (2010). Cytometry and DNA ploidy: clinical uses and molecular perspective in gastric and lung cancer. Journal of cellular physiology, 222(3), 532–539. https://doi.org/10.1002/jcp.21991

Efeyan, A., Garcia-Cao, I., Herranz, D., Velasco-Miguel, S., & Serrano, M. (2006). Tumour biology: Policing of oncogene activity by p53. Nature, 443(7108), 159. https://doi.org/10.1038/443159a

Elledge S. J. (1996). Cell cycle checkpoints: preventing an identity crisis. Science (New York, N.Y.), 274(5293), 1664–1672. https://doi.org/10.1126/science.274.5293.1664

Ellenson L.H., Pirog E.C. In: Robbins and Cotran Pathologic Basis of Disease. 9th ed. Kumar V., Abbas A.K., Aster J.C., editors. Elsevier/Saunders; 2015. The female genital tract; pp. 280-296

Esteller, M., Catasus, L., Matias-Guiu, X., Mutter, G. L., Prat, J., Baylin, S. B., & Herman, J. G. (1999). hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. The American journal of pathology, 155(5), 1767–1772. https://doi.org/10.1016/S0002-9440(10)65492-2

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013

Kanaya, T., Kyo, S., Sakaguchi, J., Maida, Y., Nakamura, M., Takakura, M., Hashimoto, M., Mizumoto, Y., & Inoue, M. (2005). Association of mismatch repair deficiency with PTEN frameshift mutations in endometrial cancers and the precursors in a Japanese population. American journal of clinical pathology, 124(1), 89–96. https://doi.org/10.1309/PAACLG8DXDK0X2B1

Kunkel, T. A., & Erie, D. A. (2005). DNA mismatch repair. Annual review of biochemistry, 74, 681–710. https://doi.org/10.1146/annurev.biochem.74.082803.133243

Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1998). Genetic instabilities in human cancers. Nature, 396(6712), 643–649. https://doi.org/10.1038/25292

Levine A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell, 88(3), 323–331. https://doi.org/10.1016/s0092-8674(00)81871-1

Mitchell, J. R., Hoeijmakers, J. H., & Niedernhofer, L. J. (2003). Divide and conquer: nucleotide excision repair battles cancer and ageing. Current opinion in cell biology, 15(2), 232–240. https://doi.org/10.1016/s0955-0674(03)00018-8

Murray A. W. (1995). The genetics of cell cycle checkpoints. Current opinion in genetics & development, 5(1), 5–11. https://doi.org/10.1016/s0959-437x(95)90046-2

Negrini, S., Gorgoulis, V. G., & Halazonetis, T. D. (2010). Genomic instability--an evolving hallmark of cancer. Nature reviews. Molecular cell biology, 11(3), 220–228. https://doi.org/10.1038/nrm2858

Palmero, I., Pantoja, C., & Serrano, M. (1998). p19ARF links the tumour suppressor p53 to Ras. Nature, 395(6698), 125–126. https://doi.org/10.1038/25870

Paulovich, A. G., Toczyski, D. P., & Hartwell, L. H. (1997). When checkpoints fail. Cell, 88(3), 315–321. https://doi.org/10.1016/s0092-8674(00)81870-x

Rao, C. V., Yamada, H. Y., Yao, Y., & Dai, W. (2009). Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice. Carcinogenesis, 30(9), 1469–1474. https://doi.org/10.1093/carcin/bgp081

Riedel, C. G., Katis, V. L., Katou, Y., Mori, S., Itoh, T., Helmhart, W., Gálová, M., Petronczki, M., Gregan, J., Cetin, B., Mudrak, I., Ogris, E., Mechtler, K., Pelletier, L., Buchholz, F., Shirahige, K., & Nasmyth, K. (2006). Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature, 441(7089), 53–61. https://doi.org/10.1038/nature04664

Shi Y. (2009). Serine/threonine phosphatases: mechanism through structure. Cell, 139(3), 468–484. https://doi.org/10.1016/j.cell.2009.10.006

Sieber, O., Heinimann, K., & Tomlinson, I. (2005). Genomic stability and tumorigenesis. Seminars in cancer biology, 15(1), 61–66. https://doi.org/10.1016/j.semcancer.2004.09.005

Tang, Z., Shu, H., Qi, W., Mahmood, N. A., Mumby, M. C., & Yu, H. (2006). PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Developmental cell, 10(5), 575–585. https://doi.org/10.1016/j.devcel.2006.03.010

Tashiro, H., Katabuchi, H. (2014). The Relationship Between Estrogen and Genes in the Molecular Pathogenesis of Endometrial Carcinoma. Curr Obstet Gynecol Rep 3, 9–17. https://doi.org/10.1007/s13669-013-0074-3

Yao, Y., & Dai, W. (2014). Genomic Instability and Cancer. Journal of carcinogenesis & mutagenesis, 5, 1000165. https://doi.org/10.4172/2157-2518.1000165

Zhang, X. P., Liu, F., & Wang, W. (2011). Two-phase dynamics of p53 in the DNA damage response. Proceedings of the National Academy of Sciences of the United States of America, 108(22), 8990–8995. https://doi.org/10.1073/pnas.1100600108

Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F. (1998). Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes & development, 12(15), 2424–2433. https://doi.org/10.1101/gad.12.15.2424