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Increase, Chromosomal aberrations leads to Increase, Cell Proliferation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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. 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 Supporting this KER
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
Uncertainties in this KER are as follows:
- 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).
- 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).
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 modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability pertains to all multicellular organisms, as cell proliferation and death regulate tissue homeostasis (Pucci et al., 2000).
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