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Relationship: 1979


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Chromosomal aberrations leads to Increase, Cell Proliferation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Deposition of energy leading to lung cancer adjacent Moderate Low Brendan Ferreri-Hanberry (send email) Open for citation & comment WPHA/WNT Endorsed
Deposition of energy leading to occurrence of cataracts adjacent Moderate Low Arthur Author (send email) Open for citation & comment

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

CAs are defined as abnormalities in the chromosome structure, often due to losses or gains of chromosome sections or the entire chromosomes itself, or chromosomal rearrangements (van Gent et al., 2001). These aberrant structures can come in a multitude of different forms. Types of CAs include: inversions, insertions, deletions, translocations, dicentric chromosomes (chromosomes that contain two centromeres, often resulting from telomere end fusions (Fenech & Natarajan 2011; Rode et al., 2016), centric ring chromosomes, acentric chromosome fragments, micronuclei (MN; small nucleus-like structures containing entire chromosomes or chromosome fragments (Fenech & Natarajan, 2011; Doherty et al., 2016), nucleoplasmic bridges (NBPs; a corridor of nucleoplasmic material containing chromatin that is attached to both daughter cell nuclei), nuclear buds (NBUDs; small MN-type structures that are still connected to the main nucleus (Fenech & Natarajan, 2011), and copy number variants (CNVs; deletions or duplications of chromosome segments (Russo et al., 2015).

If these CAs affect genes involved in controlling the cell cycle, this may result in increased cellular proliferation. CAs arising from cell transformation can lead to stalling in cell replication to initiate repair (Jackson et al., 2009). CAs can also cause a loss of cell cycle checkpoints resulting in cell proliferation due to the entry into S-phase of the cell cycle   (Jackson et al., 2009; Hanahan & Weinburg, 2011). There are three types of genes that, if modified, may result in high rates of proliferation: proto-oncogenes, tumour suppressor genes (TSGs), and caretaker/stability genes (Vogelstein & Kinzler, 2004; Hanahan & Weinberg, 2011). Furthermore, gene fusions that result from CAs have also been implicated in augmenting cellular proliferation (Sanders & Albitar, 2010; Ghazavi et al., 2015; Kang et al., 2016).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

There is a strong biological plausibility for a relationship between CAs and rates of cellular proliferation. This is particularly emphasized in the context of carcinogenesis, as high cellular proliferation is a known hallmark of cancer, and an enabling characteristic of increased proliferation is genomic instability (Hanahan & Weinberg, 2011).Topical reviews are available documenting the contribution of CAs to cellular proliferation and/or cancer development  (Mes-Masson & Witte, 1987; Bertram, 2001; Vogelstein & Kinzler, 2004; Ghazavi et al. ,2015; Kang et al., 2016). The link between chromosomal instability (CIN), which describes the rate of chromosome gains and losses, and cancer development has also been well documented (Thompson et al., 2017; Gronroos, 2018; Targa & Rancati, 2018; Lepage et al., 2019).

Many CAs are thought to be formed through two main mechanisms: inadequate repair of DNA damage, and errors in mitosis. If there is damage to the DNA that the cell is unable to properly repair, the unrepaired lesion may translate into a CAs (Bignold, 2009; Danford, 2012; Schipler & Iliakis, 2013); the type of resulting CA is often influenced by the cell cycle stage when the damage occurred (Danford, 2012; Registre et al., 2016; Vodicka et al., 2018), and the type of erroneous repair (Ferguson & Alt, 2001; Povirk, 2006; Bignold, 2009; Danford, 2012; Schipler & Iliakis, 2013). Errors made during repair may be particularly detrimental if they interrupt or modify critical genes, or if chromosome structures are created that cannot undergo mitosis (Schipler & Iliakis, 2013). Similarly, errors in mitosis that prevent chromosomes from being properly segregated may also lead to CAs. These errors could be due to by improper timing of centrosome separation, the presence of extra centrosomes, inappropriate mitotic spindle assembly and attachment to kinetochores (found on the centromeres), and incorrect sister-chromatid cohesion (Levine & Holland, 2018).

The presence of CAs in cells may be particularly detrimental if they alter the rate of cellular proliferation by affecting  genes that control the cell cycle, namely proto-oncogenes, TSGs (Bertram, 2001; Vogelstein & Kinzler, 2004) or caretaker/stability genes (Vogelstein & Kinzler, 2004). Proto-oncogenes are genes that, when activated, promote cellular proliferation. CAs that increase activation of these genes may aberrantly boost cell cycling and therefore increase proliferation (Bertram, 2001; Vogelstein & Kinzler, 2004). Activation of proto-oncogenes have also been implicated in the cancer stem cell theory of carcinogenesis (Vicente-duen et al., 2013). Examples or proto-oncogenes include EGFR and KRAS (Sanders & Albitar, 2010). TSGs refer to genes that actively suppress cell proliferation and, in some cases, promote apoptosis (Bertram, 2001; Vogelstein & Kinzler, 2004; Sanders & Albitar, 2010). If these genes are silenced by CAs, this may remove cell cycle checkpoints, thus allowing for unhindered cellular proliferation and decreased apoptosis (Bertram, 2001; Vogelstein & Kinzler, 2004). Common TSGs are TP53 and RB (Hanahan & Weinberg, 2011). Lastly, caretaker/stability genes are those involved in the prevention and detection of DNA damage, and the instigation and completion of the required DNA repair (Vogelstein & Kinzler, 2004; Hanahan & Weinberg, 2011). If the function of these caretaker/stability genes is affected by CAs, this may result in genome-wide inadequate DNA repair, which in turn may result in genetic damage to TSGs or proto-oncogenes (Vogelstein & Kinzler, 2004). Genes involved in mismatch repair (MMR), nucleotide-excision repair (NER) and base-excision repair (BER) are all examples of caretaker/stability genes (Vogelstein & Kinzler, 2004). 

There are also other CAs commonly associated with cancer. In prostate cancer, truncated TSGs such as TP53, PTEN, BRCA1, and BRCA2 are a result of chromosomal rearrangements (Mao et al., 2011). Similarly, chromosomal inversions were found to be responsible for just over half of the RET gene fusions associated with lung adenocarcinoma samples (Mizukami et al., 2014).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties in this KER are as follows:

  1. A study using peripheral blood lymphocytes isolated from head and neck cancer patients found significantly increased CAs (including chromosome-type aberrations, chromatid-type aberrations, dicentric chromosomes, aneuploidy, MN, NPBs and NBUDs) relative to healthy controls. In the lymphocytes from these same cancer patients, however, the cell proliferation rates were significantly decreased (George et al., 2014).
  2. Characterization of 20 different ameloblastomas, which are benign tumours associated with the jaw, found low CAs frequencies and low rates of cellular proliferation (Jääskeläinen et al., 2002).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Not established.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Not established.

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Studies that directly assessed the time scale between CAs and cellular proliferation were not identified. However, differences in cellular proliferation rates for cells with different CA-related manipulations or treatments were evident within the first 3 days of culture (Stopper et al., 2003; Li et al., 2007; Soda et al., 2007; Irwin et al., 2013; Guarnerio et al., 2016). More studies are required, however, to formulate a detailed time scale relating these two events.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not established.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The domain of applicability pertains to all multicellular organisms, as cell proliferation and death regulate tissue homeostasis (Pucci et al., 2000).


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

Bertram, J.S. (2001), "The molecular biology of cancer.", Mol. Aspects. Med. 21:166–223. doi:10.1016/S0098-2997(00)00007-8.

Bignold, L.P. (2009), "Mechanisms of clastogen-induced chromosomal aberrations: A critical review and description of a model based on failures of tethering of DNA strand ends to strand-breaking enzymes.", Mutat. Res., 681(2-3):271–298. doi:10.1016/j.mrrev.2008.11.004.

Danford, N. (2012), "The Interpretation and Analysis of Cytogenetic Data.", Methods Mol. Biol., 817:93-120. doi:10.1007/978-1-61779-421-6.

Doherty, A., S.M. Bryce & J.C. Bemis (2016), "The In Vitro Micronucleus Assay. Methods in molecular biology", (Clifton, N.J.). 817:121-41. doi: 10.1007/978-1-61779-421-6_7.

Fenech, M. & A.T. Natarajan (2011), "Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells.", Mutagenesis 26(1):125–132. doi:10.1093/mutage/geq052.

Ferguson, D.O. & F.W. Alt (2001), "DNA double strand break repair and chromosomal translocation: Lessons from animal models.", Oncogene 20(40):5572–5579.

Fowlis, D.J. & A. Balmain (1993), "Oncogenes and Tumour Suppressor Genes in Transgenic Mouse Models of Neoplasia.", Eur. J. of Cancer 29A(4):638-45. doi: 10.1016/S0959-8049(05)80170-4.

van Gent D.C., J.H.J. Hoeijmakers & R. Kanaar (2001), "Chromosomal stability and the DNA double-stranded break connection.", Nat. Rev. Genet. 2(3):196–206. doi:10.1038/35056049.

George, A., R. Dey & V.B. Dqhumhh (2014), "Nuclear Anomalies, Chromosomal Aberrations and Proliferation Rates in Cultured Lymphocytes of Head and Neck Cancer Patients.", Asian Pacific journal of cancer prevention. 15(3):1119-1123. doi:10.7314/APJCP.2014.15.3.1119.

Ghazavi, F. et al. (2015), "Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia.", Exp Hematol. 43(8):640–653. doi:10.1016/j.exphem.2015.05.015.

Gronroos, E. (2018), "Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities.", Cancer Res. 78(23):6529-6535, doi:10.1158/0008-5472.CAN-18-1958.

Guarnerio, J. et al. (2016), "Oncogenic Role of Fusion-circRNAs Derived from Article Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations.", Cell. 165(2):289–302. doi:10.1016/j.cell.2016.03.020.

Hanahan, D. & R.A. Weinberg (2011), "Review Hallmarks of Cancer: The Next Generation.", Cell. 144(5):646–674. doi:10.1016/j.cell.2011.02.013.

Irwin, M.E. et al. (2013), "Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome – Positive Acute Lymphoblastic Leukemia.", PLoS One, 8(8):1–10. doi:10.1371/journal.pone.0070608.

Jääskeläinen, K. et al. (2002), "Cell proliferation and chromosomal changes in human ameloblastoma.", Cancer Genetics and Cytogenetics. 136(1):31-7. doi: 10.1016/S0165-4608(02)00512-5.

Jackson, S. P., and& Bartek, J. (2009),. “The DNA-damage response in human biology and disease.” Nature, 461(7267), 1071–1078.    

Kang, Z.J. et al. (2016), "The Philadelphia chromosome in leukemogenesis.", Chin J Cancer.:1–15. doi:10.1186/s40880-016-0108-0.

Lepage, C.C. et al. (2019), "Detecting Chromosome Instability in Cancer: Approaches to Resolve Cell-to-Cell Heterogeneity.", Cancers (Basel), 11(2): pii: E226. doi:10.3390/cancers11020226.

Levine, M.S. & A.J. Holland (2018), "The impact of mitotic errors on cell proliferation and tumorigenesis.", Genes Dev., 32(9-10):620–638. doi:10.1101/gad.314351.118.620.

Li, H. et al. (2007), "Effects of rearrangement and allelic exclusion of JJAZ1 / SUZ12 on cell proliferation and survival.", PNAS, 104(50):20001–20006.

Mao, X. et al. (2011), "Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer.", American Journal of Cancer Research. 1(5):604-17.

Mes-Masson, A.-M. & O.N. Witte (1987), "Role of The abl Oncogene in Chronic Myelogenous Leukemia.", Advances in Cancer Research. 49:53-74. doi: 10.1016/S0065-230X(08)60794-0.

Mitelman, F. (2005), "Deep Insight Section: Cancer cytogenetics update", Atlas of Genetic and Cytogenetics in Oncology and Haematology,  9(2):188–190. doi:10.4267/2042/38202.

Mizukami, T. et al. (2014), "Molecular Mechanisms Underlying Oncogenic RET Fusion in lung adenocarcinoma.", J Thorac Oncol. 9(5):622–630. doi:10.1097/JTO.0000000000000135.

Povirk, L.F. (2006), "Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks.", DNA Repair (Amst). 5(9-10):1199–1212. doi:10.1016/j.dnarep.2006.05.016.

Pucci, B., M. Kasten & A. Giordano (2000), "Cell Cycle and Apoptosis 1", Neoplasia, 2(4):291–299.doi: 10.1038/sj.neo.7900101

Registre, M., R. Proudlock & N. Carolina (2016), "The In Vitro Chromosome Aberration Test.", Genetic Toxicology Testing. 207-267. doi: 10.1016/B978-0-12-800764-8.00007-0.

Rode, A. et al. (2016), "Chromothripsis in cancer cells: An update.", Int. J. Cancer, 138(10):2322–2333. doi:10.1002/ijc.29888.

Russo, A. et al. (2015), "Review Article Genomic Instability: Crossing Pathways at the Origin of Structural and Numerical Chromosome Changes.", Envrion. Mol. Mutagen. 56(7):563-580. doi:10.1002/em.

Sanders, H.R. & M. Albitar (2010), "Somatic mutations of signaling genes in non-small-cell lung cancer.", Cancer Genet Cytogenet. 203(1):7–15. doi:10.1016/j.cancergencyto.2010.07.134.

Schipler, A. & G. Iliakis (2013), "DNA double-strand – break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.", Nucleic Acids Res., 41(16):7589–7605. doi:10.1093/nar/gkt556.

Soda, M. et al. (2007), "Identification of the transforming EML4 – ALK fusion gene in non-small-cell lung cancer.", Nature, 448(7153):561-566. doi:10.1038/nature05945.

Stopper, H. et al. (2003), "Increased cell proliferation is associated with genomic instability: elevated micronuclei frequencies in estradiol-treated human ovarian cancer cells.", Mutagenesis 18(3):243-247. doi:10.1093/mutage/18.3.243.

Targa, A. & G. Rancati (2018), "Cancer: a CINful evolution.", Curr Opin Cell Biol. 2018 Jun;52:136-144., doi:10.1016/

Thompson, L.L. et al. (2017), "Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer.", Cancers (Basel), 9(11): pii: E151 doi:10.3390/cancers9110151.

Vicente-Duenas, C. et al. (2013), "Function of oncogenes in cancer development: a changing paradigm", EMBO J., 32(11):1502–1513. doi:10.1038/emboj.2013.97.

Vodicka, P. et al. (2018), "Genetic variation of acquired structural chromosomal aberrations.", Mutat Res Gen Tox En, 836(May):13–21. doi:10.1016/j.mrgentox.2018.05.014.

Vogelstein, B. & K.W. Kinzler (2004), "Cancer genes and the pathways they control.", Nat. Med, 10(8):789–799. doi:10.1038/nm1087.