Chromosome segregation errors: a double-edged sword - TI Pharma

2.2 Benefits of being CIN
Generally, CIN is thought to be able to promote tumorigenesis by inducing loss of certain tumor
suppressor genes or gain of oncogenes. Loss of heterozygosity could reveal certain mutations in
tumor suppressor genes and therefore promote a transforming event 634 . In line with this, crossing
a CIN mouse model carrying a hypomorphic Bub1 allele with several tumor-prone mouse models
resulted in the loss of tumor suppressor genes, such as p53 and APC 286 . Chromosome segregation
errors could indeed be quite effective in inducing LOH, since it will immediately induce loss of multiple
genes. However, the induction of aneuploidy is very likely to be detrimental to cells 292,294,445,446 and
it is therefore thought that coinciding mutations would have to arise in other pathways to render
cells insensitive to changes in chromosome number. Examples of such mutations are loss of p53
function 431 or mutations that promote proteasomal degradation in order to circumvent the increases
in protein production obtained by gains of chromosomes 538 . These mutations on their turn could
allow the induction of other transforming changes, which ultimately could lead to tumorigenesis.
Another interesting hypothesis on how CIN and aneuploidy could promote tumorigenesis is through
the creation of a mutator phenotype 281,635 . Aneuploidy could, by changing levels of certain DNA repair
genes, promote an increase in genomic instability. In line with this hypothesis, aneuploidy was initially
found to correlate with genomic instability in cancer cells 617 and has recently been shown to indeed
induce genomic instability in budding yeast 388 . Moreover, CIN could itself be a mutator by inducing
DNA damage and structural chromosomal changes through micronuclei formation 390 or cleavage
furrow ingression in the presence of lagging chromosomes (Chapter 2). Interestingly, crossing a CIN
mouse model with a mouse model deficient for the DNA damage checkpoint kinase ATM resulted
in accelerated tumor formation 407 , suggesting that loss of DNA damage checkpoint activation could
promote CIN-induced tumor formation, again supporting a role for CIN in promoting genomic instability.
Interestingly, CIN and defects in mismatch repair, which result in microsatellite instability (MIN), were
found to be almost always mutually exclusive in colon carcinoma cells 270 . MIN tumor cells are near
diploid, indicating that aneuploidy is not simply a bystander of tumor formation 270 . In contrast to
MIN cells, CIN cells rarely obtain mismatch repair deficiencies, but are always aneuploid, suggesting
that CIN and MIN each support a distinct mutator phenotype driving cancer progression 231 .
In summary, CIN and aneuploidy could together create an environment in which cancer cells
continuously lose and gain whole chromosomes, but also gain mutations or translocations, which
interfere with the function of genes involved in DNA repair, mitotic fidelity and cell cycle progression,
therefore promoting transformation of cells or conferring resistance to chemotherapeutics.
2.3 Future of CIN research
The question remains whether CIN is an initiator of tumorigenesis, whether it mainly provides an
enhancing effect to promote transformation or if it is a mere consequence of tumor formation.
The fact that CIN is a common trait of over 70% of all tumors makes it unlikely to simply be a
bystander of tumorigenesis. Whole genome sequencing of early neoplasia in either tumorprone
mouse models or human patients in combination with assessment of CIN status could provide
answers to the question whether CIN has an initiating or enhancing role in tumorigenesis.
The presence of CIN or aneuploidy in early neoplasia in the absence of any other mutations,
would suggest that CIN is an initiating event. In contrary, frequent mutations in certain
oncogenes or tumor suppressor genes in the absence of any CIN, would suggest that
CIN occurs later during tumor development and is rather an enhancer of tumorigenesis.
Ideally, mitotic progression or aneuploidy status would be visualized live in mouse models for spontaneous
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Discussion
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