Chromosome Instability (CIN), Aneuploidy and Cancer

Abstract

Chromosome instability (CIN) describes an increased rate of chromosome missegregation in mitosis resulting in a failure to maintain the correct chromosomal complement (euploidy). The aberrant chromosomal state of a cell can be classified based on the changes in ploidy, gain or loss of whole chromosomes (aneuploidy) or gross chromosomal rearrangements (GCR), all of which are hallmarks of solid cancers. CIN can be caused by multiple mechanisms involved in chromosome segregation, including a weakened or overactivated mitotic spindle assembly checkpoint, sister chromatid cohesion defects, increased merotelic kinetochore‐microtubule attachments or the presence of extra centrosomes. CIN occurs early in cancer development, and is associated with poor prognosis. CIN has long been proposed to contribute to tumour progression. However, recent studies suggest that CIN can either promote or suppress tumour progression, depending on the contexts. Targeting characteristics specific to tumour cells, such as CIN, is an attractive therapeutic avenue.

Key Concepts:

  • Stable aneuploidy can occur without CIN (e.g. Down syndrome patients with trisomy chromosome 21), but aneuploidy observed in cancer is often caused by CIN.

  • CIN is a hallmark of solid cancers, occurring early in tumorigenesis, and is associated with poor prognosis.

  • CIN can arise from defects that affect different steps of chromosome segregation, including the spindle checkpoint, kinetochore‐microtubule attachments, sister chromatid cohesion, centrosome duplication and bipolar spindle assembly.

  • Mutations and misregulation of genes functioning at the spindle checkpoint, at the kinetochore, sister chromatid cohesion and centrosomes are associated with various cancer types.

  • Germline biallelic mutations in spindle checkpoint gene BUB1B are associated with mosaic variegated aneuploidy (MVA) and predispositions to various types of cancer, strongly supporting a causal link between CIN and cancer development. However, only low frequency of somatic mutations in spindle checkpoint components has been found in spontaneous cancers.

  • Either a weakened spindle checkpoint or a prolonged activated checkpoint can cause chromosome missegregation, presumably due to premature sister chromatid separation or increased frequency of uncorrected merotelic attachments, respectively.

  • Extra centrosomes usually cluster to form bipolar spindles, but they undergo a transient multipolar stage, increasing the frequency of merotelic attachments and lagging chromosomes.

  • Animal models with CIN can either promote or suppress cancers, depending on the genetic background and contexts.

  • Stable aneuploidy per se does not cause CIN, and is antiproliferative.

  • CIN can be exploited as a cancer‐specific target for selective killing of tumours.

Keywords: chromosome instability; aneuploidy; mitosis; chromosome segregation; mitotic spindle checkpoint; kinetochore‐microtubule attachment; sister chromatid cohesion; centrosomes; tumour heterogeneity; tumour prognosis

Figure 1.

Progression of mitosis and the role of the spindle checkpoint. (a) After DNA replication in S phase, sister chromatids are held together by the cohesin complex, enriched at the centromeric region until anaphase. During prometaphase, microtubules emanating from each centrosome search and capture the sister kinetochores. The spindle checkpoint proteins detect and bind to any unattached kinetochores, and send an inhibitory signal to the anaphase‐promoting complex/cyclosome (APC/C). An APC/C target, Securin, can bind to and inhibit Separase, a protease that cleaves the cohesin complex. This delays the progression of mitosis to allow more time for correcting kinetochore‐microtubule attachments. (b) When all sister kinetochores achieve bipolar attachments during metaphase, the spindle checkpoint is turned off. The APC/C ubiquitinates Securin, which is then targeted for degradation. Separase is now released from Securin. (c) In anaphase, Separase cleaves a component of the cohesin complex, allowing the separation of sister chromatids.

Figure 2.

Different mechanisms leading to chromosome missegregation. (a) A weakened spindle checkpoint leads to premature sister chromatid separation. Any unattached chromosome will be randomly segregated or lost. (b) Similarly, precocious sister chromatid separation may cause sister chromatids to attach to the same pole or not attach at all, resulting in chromosome gain or loss. (c) Recovery from a prolonged overactivated checkpoint increases the frequency of merotelic attachments. This results in lagging chromosomes during anaphase and can cause chromosome loss. Lagging chromosomes can also block furrow progression, and results in tetraploidy. (d) The presence of extra centrosomes form multipolar spindles, which often cluster to allow bipolar orientation. However, this increases the frequency of merotelic attachments as in the case of checkpoint overactivation.

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Yuen, Karen Wing Yee(Oct 2010) Chromosome Instability (CIN), Aneuploidy and Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022413]