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Cancer & Chromosome biology > Aneuploidy > Flashcards

Aneuploidy Flashcards

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1
Q

what is aneuploidy?

A

it is a number of chromosomes different from the usual 46 (in case of human cells)

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2
Q

give an example of aneuploidy which is not cancer

A

in Downs syndrome (aka trisomy 21), the total number of chromosomes in a cell is 47

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3
Q

give an example of aneuploidy which is not cancer

A

in Downs syndrome (aka trisomy 21), the total number of chromosomes in a cell is 47

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4
Q

what percentage of solid tumojurs and heamatoligical malignancies have aneuploidy?

A

90% of solid tumours
60% of haematological malignancies

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5
Q

how does aneuploidy arise?

breifly

A

aneuploidy arises from the mis-segregation of whole chromsomes during cell division

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6
Q

why is there a great variety of karytotypes within a cell population in one or the same tumour?

A

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

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7
Q

what is chromosomal instability (CIN)?

A

Lack of capacity to maintain the same number of chromosomes from one generation of cells to the next

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8
Q

whats the difference between aneuploidy and CIN

A

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

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9
Q

what are the consequences of aneuploidy?

A

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

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10
Q

what is the most frequent effect of aneuploidy?

A

cell death

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11
Q

what are the three things that come after aneuploidy arises?

A

aneuploidy selected out (negative selection)
aneuploidy maintained (neutral selection)
aneuploidy spreads (positive selection)

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12
Q

give an example of how aneuploidy may participate in cancer evolution

after treatment

A

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

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12
Q

give an example of how aneuploidy may participate in cancer evolution

after treatment

A

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

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13
Q

how do CIN and aneuploidy drive cancer evolution?

A

genomic/genetic instability helps to pass through narrow environmental contraints

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14
Q

what may be the origins of aneuploidy?

5

A
  1. errors in kinetochore-microtubules attachments
  2. supernumerary chromosomes
  3. weak spindle assemble checkpoint fails to delay anaphase
  4. impaired sister chromatid cohesion
  5. cytokinesis failure
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15
Q

at the cellular level __ chromsomes are thought to be the reason of aneuploidy

A

lagging chomosomes

16
Q

what are the four major forms of attachment to microtubules to chromosomes?

A

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

17
Q

what is a micronucleus and why does it form?

A

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

18
Q

what happens when a cell has supernumerary centrosomes?

A

(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

19
Q

why do multipolar spindles become bipolar?

A

due to centrosome clustering

20
Q

how do supernumeary centrosome cause chromosome missegregation?

breifly

A

by increasing the rates of formation of merotelic attachments

21
Q

How does cytokinesis failure lead to tetroploidy

A

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

22
Q

what is chromothripsis?

A

massive genomic rearrangmenets by pulverising chromosome into very small pieces then stiching back together
cause structural aberrations

23
Q

give some examples of simple chromosomal rearrangements

A

Intrachromosomal structural variations
Interchromosomal structural variations
Unbalanced translocation

24
Q

give an example of an extreme chromosomal rearrangment that causes structural aberrations

A

chromothripsis

25
Q

what is the relationship between micronuclei and chromothripsis?

A

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

26
Q

why can aneuploidy be used to fight cancer?

A

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

Cancer & Chromosome biology (10 decks)

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