Aneuploidy Flashcards
what is aneuploidy?
it is a number of chromosomes different from the usual 46 (in case of human cells)
give an example of aneuploidy which is not cancer
in Downs syndrome (aka trisomy 21), the total number of chromosomes in a cell is 47
give an example of aneuploidy which is not cancer
in Downs syndrome (aka trisomy 21), the total number of chromosomes in a cell is 47
what percentage of solid tumojurs and heamatoligical malignancies have aneuploidy?
90% of solid tumours
60% of haematological malignancies
how does aneuploidy arise?
breifly
aneuploidy arises from the mis-segregation of whole chromsomes during cell division
why is there a great variety of karytotypes within a cell population in one or the same tumour?
it is thought to be related to the very high genomic instability and a lage number of cellls, which die because their chromosome number and/or structure does not allow certain cells to survive and proliferate
what is chromosomal instability (CIN)?
Lack of capacity to maintain the same number of chromosomes from one generation of cells to the next
whats the difference between aneuploidy and CIN
Aneyploidy is an acquired state of a cell
CIN is a process that may lead to aneuploidy and that may be driven by aneuploidy
not all aneuploid cells must show chromosomal instability, and not all cells that are charaterised by CIN must aneuploid
what are the consequences of aneuploidy?
effect on gene expression and protein level
effect on cell fitness and proliferation (impaired proliferation and metabolism)
induce chromosomal instability
produces heterogenity in a cell population via CIN (makes pop. more adaptable to a broader spectrum of environmenal challengers)
may contribute to better survival of cellls
what is the most frequent effect of aneuploidy?
cell death
what are the three things that come after aneuploidy arises?
aneuploidy selected out (negative selection)
aneuploidy maintained (neutral selection)
aneuploidy spreads (positive selection)
give an example of how aneuploidy may participate in cancer evolution
after treatment
genome instability driven by aneuploidy may facilitate chemoresistance
resistance to chemotherapy is dictated by change in gene copy number and altered expression of specific proteins
chromosomes segregation errors lead tohigh karyotype heterogeneity which leads to cell proliferation
low karyotype heterogeneity will lead to cell death
give an example of how aneuploidy may participate in cancer evolution
after treatment
genome instability driven by aneuploidy may facilitate chemoresistance
resistance to chemotherapy is dictated by change in gene copy number and altered expression of specific proteins
chromosomes segregation errors lead tohigh karyotype heterogeneity which leads to cell proliferation
low karyotype heterogeneity will lead to cell death
how do CIN and aneuploidy drive cancer evolution?
genomic/genetic instability helps to pass through narrow environmental contraints
what may be the origins of aneuploidy?
5
- errors in kinetochore-microtubules attachments
- supernumerary chromosomes
- weak spindle assemble checkpoint fails to delay anaphase
- impaired sister chromatid cohesion
- cytokinesis failure
at the cellular level __ chromsomes are thought to be the reason of aneuploidy
lagging chomosomes
what are the four major forms of attachment to microtubules to chromosomes?
Amphitelic – bi orientated (correct tension & inactive SAC)
Monotelic – only one attached to one side. Will signal stop (incorrect tension & active SAC)
Syntelic – one kinetochore not properly attached to either one (no tension & SAC active)
Merotelic – one kinetochore attached to one, the other is attached to both. SAC does not sense this as an incorrect attachment so stays inactive as there is tension
if too many to repair then leads to chromosomal mis-segregation
what is a micronucleus and why does it form?
small DNA-containing nuclear structures that are spatially isolated from the main nucleus.
separation of merotelic attachments so late so that the nucelar enveliope starts to reform but the lagging chromsome is left out
what happens when a cell has supernumerary centrosomes?
(Supernumerary centromsomes very varely lead to multipolar divisions. Even if they do, typically cells die after such division)
Instead, supernumerary centrosomes lead to formation of multipolar spindles, which later convert to bipolar ones, but merotelic attachments are formed and persist leading to mis-segegation
why do multipolar spindles become bipolar?
due to centrosome clustering
how do supernumeary centrosome cause chromosome missegregation?
breifly
by increasing the rates of formation of merotelic attachments
How does cytokinesis failure lead to tetroploidy
Diploid (2n) cells undergo bipolar mitosis with cytokinesis failure leading to binucleated tetraploid (2 × 2n) cells, which generate mononucleated tetraploid (4n) cells through normal bipolar mitosis. Subsequent proliferation of mononucleated tetraploid cells results in more tetraploid ones.
promotes tumourigenesis and CIN
what is chromothripsis?
massive genomic rearrangmenets by pulverising chromosome into very small pieces then stiching back together
cause structural aberrations
give some examples of simple chromosomal rearrangements
Intrachromosomal structural variations
Interchromosomal structural variations
Unbalanced translocation
give an example of an extreme chromosomal rearrangment that causes structural aberrations
chromothripsis
what is the relationship between micronuclei and chromothripsis?
chromosome missegregation leads to formation of micronuclei
DNA replication in micronuclei is defective
this leads to extensive damage of DNA in micronuclei
Micronuclear chromosomes undergo chromothripsis
Some of the rearranged DNA is incorporated back into the genome
why can aneuploidy be used to fight cancer?
based on the observation that certain levels of aneuploidy cannot be tolerated in cells
if you synthetically increase the levels of aneuploidy above the existing levels you can cause cell death
higher magnitude of chromosome missegregation leads to cell death or cell cycle arrest
