Chromosomal Instability

Question 1

What is aneuploidy?

Answer 1

The loss or gain of entire chromosomes

Question 2

How is aneuploidy andt translocation revealed?

Answer 2

Chromosome painting/FISH - fluorescent in situ hybridisation

Question 3

Name two specific examples of aneuploidy that is reoccuring?

Answer 3

Chromosome 3 is lost in melanomas, chromosome 7 is gained in renal carcinomas

Question 4

What is the consequence of aneuploidy?

Answer 4

Gain of chromosome could give multiple copies of a oncogene, or elmination of chromosomes could give loss of TSGs. Loss of heterozygosity can result in leaving only a mutant copy of a gene present

Question 5

Losing chromosomes involves a loss of housekeeping genes, which would render the cell invalid. How is this overcome?

Answer 5

When chromosomes are lost, the hetrologous chromosome is cloned, a mutant TSG could be cloned to give 2 copies.

Question 6

Microarray chips of cancerous/non-cancerous cells shows widespread differences in protein expression. What does this suggest?

Answer 6

This could suggest a mutation in pathways that regulate expression such as MAPK, but it could also suggest aneuploidy

Question 7

Cells within a tumour have different sets of chromosomes. How does this give a mechanism for drug resistance?

Answer 7

The variety in aneuploidy gives cells with different expression patterns in key genes defining the ten hallmarks of cancer. In response to drugs targetting specific cancer cell characteristics, the cancer cell selects those cells with chromosomes sets give the best survivial against the drug for proliferation

Question 8

What are the two possible causes of CIN?

Answer 8

Numerical CIN & Structural CIN

Question 9

What are the five mitotic errors that lead to numerical CIN?

Answer 9

1) Defective chromosome cohesion; 2) Centrosome amplification; 3) Merotelic chromosome attachments; 4) Mitotic checkpoint defects; 5) Cell division failure

Question 10

How does loss of chromosome cohesion lead to numerical CIN?

Answer 10

Mutations in proteins of the chromosome cohnesion complex causes random segregation of the sister chromatids.

Question 11

Describe how centrosome amplification occurs and how this leads to numerical CIN?

Answer 11

Centrosome amplification occurs due to either incomplete mitosis, or extra amplification events with every cell cycle, as centrosome duplication is uncoupled from DNA. This leads to multiple spindles and a lack of bipolarity, giving unbalanced daughter cells.

Question 12

Cancer cells that have multiple spindles do not always undergo cell death, why?

Answer 12

The centrosomes cluster which mimics the appearance of a normal cell, promoting survival but giving small scale segration changes which result in aneuploidy

Question 13

How is this visualised?

Answer 13

GFP tagged tubulin

Question 14

How to microtubules of the spindle stably attach to kinetichores?

Answer 14

A microtubule from either side binds each only one of the pair of kinetichores.

Question 15

Cancer cells exhibit more of what type of kinetochore attachments?

Answer 15

Merotellic, where the microtubules from both sides bind one kinetichore, leading to incorrect segregation.

Question 16

Centrosome clustering is a slow process. This promotes what?

Answer 16

A higher amount of merotellic attachments to occur.

Question 17

Abnormal mitosis can lead to?

Answer 17

Cytokinesis failure, which leads to the cell exiting mitosis as a tetraploid.

Question 18

CIN can both drive and kill tumours, how?

Answer 18

CIN causes genetic instability. A heathly cells has relatively little, while a cancer cell has moderate genetic instability which promotes its survival and proliferation. If a cancer cell has high genetic instability it will be destroyed by apoptosis.