Guide Genome Instability in Cancer Development

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Given the multitude of distinct genetic lesions observed between tumour types and also between patients and even regions of the same tumour, it is likely that mechanisms driving CIN vary between, and within cancer types, and it will therefore be important to assess the mechanisms driving CIN in a cancer-specific manner. Moreover, since recent work has highlighted potential differences between some commonly used cancer cell lines and their intended tumour model, particularly in ovarian cancer Anglesio et al.

In addition to carefully selecting cell lines to analyse, it may be advisable, where feasible, to move towards the classification of CIN mechanisms from tumour samples directly isolated from patients, such as circulating tumour cells CTCs or other forms of liquid biopsy such as ascites-derived tumour cells Penner-Goeke et al.

Genome Instability & Cancer – Cabimer

Such efforts would not only alleviate concerns about applicability of tumour-derived cell lines but also allow the assessment of CIN in a temporal manner Penner-Goeke et al. This would provide an important advancement of our understanding of the dynamics of CIN during tumour evolution.

Current knowledge of how CIN varies over the lifetime of a tumour, and in response to treatment, is currently limited; however, elegant studies utilising tumour multiregion sequencing in patients before and after therapy have begun to elucidate the complex dynamics of CIN and tumour evolution over tumour lifetimes and how this may impact patient survival Murugaesu et al. Chromosomal instability predicts drug resistance and poor prognosis in multiple cancer types Swanton et al.

Chromosomal instability thus renders tumours more difficult to treat, but precise reasons for this are currently poorly defined. Chromosomally unstable cell lines derived either by direct manipulation of Mad1 levels to induce CIN Ryan et al. In addition, it is thought that chromosomal instability can act as an adaptive mechanism to allow cancer cells to widely sample a range of genotypes and phenotypes during periods of stress.

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This concept has been clearly demonstrated in single-celled organisms Rancati et al. Further, aneuploidy in murine liver cells promotes adaptation to chronic liver injury Duncan et al. Additionally, elegant work in mice models used Mad2 knockout to confer adaptive advantage by increasing chromosome mis-segregation, which promoted efficient tumour relapse following withdrawal of KRAS dependency Sotillo et al. However, it remains challenging to test these principles in controlled human cellular systems directly as this requires the ability to manipulate rates of chromosomal instability.

Three different but not necessarily mutually exclusive pathways to resistance are depicted. Innate resistance allows tumour growth to continue unchecked by the application of chemotherapy, for example, in the case of patients with non-responsive tumours. Adaptive resistance can occur if a pre-existing tumour cell or clone is present in the primary tumour that is capable of survival in the presence of chemotherapy agent.

Tumours will initially respond and regress, but relapse will occur, seeded from the resistant clones. Acquired resistance occurs when genetic or other mechanisms allowing the development of novel traits is present. Chemotherapy itself may also promote genome mutation and rearrangement to facilitate this process. Cells that chance upon a resistant phenotype are then able to seed tumour regrowth. A prediction of these distinct pathways to resistance is that the relapsed tumour may display different levels of heterogeneity or CIN depending on which pathway was most prevalent during tumour regrowth.

CIN-mediated genetic and phenotypic diversity in tumours thus has important implications for chemotherapy resistance via three possible pathways Fig. It is also possible that aneuploidy-mediated growth rate reduction seen in some models provides a quiescent state and concomitant protection from DNA damaging or other chemotherapeutics; ii acquired resistance , due to high initial substrate tumour cell population diversity generated prior to chemotherapy treatment, provides a high probability that a sub-clone is present that intrinsically carries protection against the chemotherapeutic agent used.

This might depend on a mutator phenotype that can generate genetic diversity via chromosomal instability or small-scale sequence level changes such as point mutations. This mutator capability could be either intrinsic to the initial tumour, for example tumour CIN, and might also be provided or augmented by the genome-destabilising effects of cytotoxic chemotherapeutic agents.

A key defining feature of chromosomally unstable cells is that they apparently tolerate a multitude and shifting spectrum of chromosomal defects that are strongly deleterious in normal cells Williams et al. Chromosomally unstable cells have overcome these arrest points by multiple mechanisms, some of which are beginning to be elucidated Li et al. Moreover, tumours appear to have evolved a beneficial and tolerable level of CIN.

Studies have shown that disrupting this balance can impact tumour progression. CENP-E is a key player during mitosis, essential for the correct alignment and segregation of chromosomes Yen et al.

Nuclear envelope rupture drives genome instability in cancer

Fine-tuning levels of chromosome segregation errors using CENP-E deregulation in mouse models have shown that CIN can act either as a tumour suppressor or to promote tumour formation depending on the rate of chromosome segregation errors Weaver et al. In addition to carefully selecting cell lines to analyse, it may be advisable, where feasible, to move towards the classification of CIN mechanisms from tumour samples directly isolated from patients, such as circulating tumour cells CTCs or other forms of liquid biopsy such as ascites-derived tumour cells Penner-Goeke et al.

Such efforts would not only alleviate concerns about applicability of tumour-derived cell lines but also allow the assessment of CIN in a temporal manner Penner-Goeke et al. This would provide an important advancement of our understanding of the dynamics of CIN during tumour evolution. Current knowledge of how CIN varies over the lifetime of a tumour, and in response to treatment, is currently limited; however, elegant studies utilising tumour multiregion sequencing in patients before and after therapy have begun to elucidate the complex dynamics of CIN and tumour evolution over tumour lifetimes and how this may impact patient survival Murugaesu et al.

Chromosomal instability predicts drug resistance and poor prognosis in multiple cancer types Swanton et al. Chromosomal instability thus renders tumours more difficult to treat, but precise reasons for this are currently poorly defined. Chromosomally unstable cell lines derived either by direct manipulation of Mad1 levels to induce CIN Ryan et al.

In addition, it is thought that chromosomal instability can act as an adaptive mechanism to allow cancer cells to widely sample a range of genotypes and phenotypes during periods of stress.

This concept has been clearly demonstrated in single-celled organisms Rancati et al. Further, aneuploidy in murine liver cells promotes adaptation to chronic liver injury Duncan et al.


  1. Aim and focus.
  2. Genome Instability in Cancer Development;
  3. A Librarians Guide on How to Publish.
  4. Equadiff 6.
  5. Genetic instability and oral cancer.
  6. GI — 7. Jahrestagung: Nürnberg, 26.– 28. September 1977.
  7. Carcinogenesis and Mutagenesis Testing.

Additionally, elegant work in mice models used Mad2 knockout to confer adaptive advantage by increasing chromosome mis-segregation, which promoted efficient tumour relapse following withdrawal of KRAS dependency Sotillo et al. However, it remains challenging to test these principles in controlled human cellular systems directly as this requires the ability to manipulate rates of chromosomal instability. Three different but not necessarily mutually exclusive pathways to resistance are depicted.

Innate resistance allows tumour growth to continue unchecked by the application of chemotherapy, for example, in the case of patients with non-responsive tumours. Adaptive resistance can occur if a pre-existing tumour cell or clone is present in the primary tumour that is capable of survival in the presence of chemotherapy agent. Tumours will initially respond and regress, but relapse will occur, seeded from the resistant clones.

Acquired resistance occurs when genetic or other mechanisms allowing the development of novel traits is present. Chemotherapy itself may also promote genome mutation and rearrangement to facilitate this process. Cells that chance upon a resistant phenotype are then able to seed tumour regrowth.

Deciphering cancer: Genomic instability in cancer

A prediction of these distinct pathways to resistance is that the relapsed tumour may display different levels of heterogeneity or CIN depending on which pathway was most prevalent during tumour regrowth. CIN-mediated genetic and phenotypic diversity in tumours thus has important implications for chemotherapy resistance via three possible pathways Fig. It is also possible that aneuploidy-mediated growth rate reduction seen in some models provides a quiescent state and concomitant protection from DNA damaging or other chemotherapeutics; ii acquired resistance , due to high initial substrate tumour cell population diversity generated prior to chemotherapy treatment, provides a high probability that a sub-clone is present that intrinsically carries protection against the chemotherapeutic agent used.

This might depend on a mutator phenotype that can generate genetic diversity via chromosomal instability or small-scale sequence level changes such as point mutations. This mutator capability could be either intrinsic to the initial tumour, for example tumour CIN, and might also be provided or augmented by the genome-destabilising effects of cytotoxic chemotherapeutic agents.

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A key defining feature of chromosomally unstable cells is that they apparently tolerate a multitude and shifting spectrum of chromosomal defects that are strongly deleterious in normal cells Williams et al. Chromosomally unstable cells have overcome these arrest points by multiple mechanisms, some of which are beginning to be elucidated Li et al. Moreover, tumours appear to have evolved a beneficial and tolerable level of CIN. Studies have shown that disrupting this balance can impact tumour progression.

CENP-E is a key player during mitosis, essential for the correct alignment and segregation of chromosomes Yen et al.

Fine-tuning levels of chromosome segregation errors using CENP-E deregulation in mouse models have shown that CIN can act either as a tumour suppressor or to promote tumour formation depending on the rate of chromosome segregation errors Weaver et al. This was supported by subsequent studies in breast cancer Roylance et al. These findings suggest that there may be a window of opportunity to target CIN cancers by driving them over the edge of tolerable CIN Janssen et al.

G Neutral comet assays of Fhit-deficient H lung carcinomas cells, with or without induction of Fhit expression. Comet assays were performed 48 h after ponasterone A-induction of Fhit expression. Since endogenous DSBs typically form due to DNA replication defects [20] , we asked if Fhit-deficient cells exhibit increased replication stress. To determine if DNA damage occurred specifically at sites of replication, we immunostained for phospho-ATR Ser , a kinase that localizes to stalled replication forks and initiates the S phase checkpoint [21].

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B Data obtained in A were quantified from 3 independent experiments, and statistical significance was determined using a 2-sided T-test. Bar graphs represent the means, and error bars mark the standard deviations. Box plots show quantification of Tail moments. P-values were determined using the Mann-Whitney rank sum test.

We reasoned that Fhit may either function upstream to prevent and minimize DNA replication stress or, alternatively may contribute to downstream replication fork maintenance and thereby prevent fork collapse and DSB formation. To distinguish between a role of Fhit upstream or downstream of replication stress, we treated cells with hydroxyurea for 4 h and measured comet tail moments.

Hydroxyurea causes replication fork stalling through depletion of dNTPs by inhibition of ribonucleotide reductase; thus cells treated with hydroxyurea for more than 2 h accumulate inactivated replication forks and DSBs [22] , [23]. If Fhit functions to support replication fork stability after replication stress, then hydroxyurea challenge should induce more DSBs in Fhit-deficient cells. However, hydroxyurea treated Fhit-silenced HEK cells and treated control cells exhibited similar levels of comet tail moments Figure 2E. Overall, hydroxyurea treatment resulted in equivalent tail moments in Fhit-expressing and Fhit-deficient cells, suggesting that Fhit does not function downstream of replication stress.