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Chromosome Instability (CIN), Aneuploidy and Cancer

  1. Karen Wing Yee Yuen

Published Online: 18 OCT 2010

DOI: 10.1002/9780470015902.a0022413

eLS

eLS

How to Cite

Yuen, K. W. Y. 2010. Chromosome Instability (CIN), Aneuploidy and Cancer. eLS. .

Author Information

  1. San Diego Branch and University of California, Ludwig Institute for Cancer Research, La Jolla, California, USA

Publication History

  1. Published Online: 18 OCT 2010

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