3rd Feb - Aneuploidy, CIN and Mitotic errors

Question 1

What is aneuploidy?

Answer 1

The presence of an abnormal number of chromosomes in the cell

Question 2

How can aneuploidy be detected?

Answer 2

By FISH on the whole karyotype

Question 3

What is the most common genetic change associated with cancer?

Answer 3

Aneuploidy present in >90% of cancers

Question 4

Give an example of a common aneuploidy in cancer

Answer 4

Chr 3 in melanomas

Chr 7 in renal carcinomas

Question 5

What is CIN?

Answer 5

Chromosome instability - a type of genomic instability in which chromosomes are unstable such that whole or parts of chromosomes are duplicated/deleted, over generations

Question 6

What does CIN cause?

Answer 6

Different cells within the tumour have quite different sets of chromosomes

Question 7

What are the two different forms of CIN?

Answer 7

Numerical

Structural

Question 8

What causes numerical CIN?

Answer 8

Results from errors in chromosome segregation during mitosis such as:

• Defective chromosome cohesion
• Centrosome amplification
• Merotelic chromosome attachments
• Mitotic checkpoint defects
• Cell division failure

Question 9

What causes structural CIN?

Answer 9

Could result from mitotic errors or pre-mitotic errors such as replication stress

Question 10

How are sister chromatids held together?

Answer 10

They must be held together from S phase to anaphase
They are held together by cohesion complexes: SCC1, SCC3, SMC1 and SMC3 which form a ring around the sister chromatids. They are loaded onto chromsomes at the beginning of the cell cycle.

Question 11

Outline common mutations causing loss of sister chromatid cohesion

Answer 11

Mutations in cohesin are common in colorectal cancer

Inactivating mutations in SCC3 cause premature loss of cohesion

Question 12

How do cancer cells acquire multiple centrosomes?

Answer 12

Uncoupling of centrosome duplication from the cell cycle

Failure of cells to divide during mitosis

Question 13

How have cancer cells adapted to prevent cell death from chromosome missegregation caused by centrosome amplification?

Answer 13

Centrosome clustering causes multiple centrosomes to cluster creating pseudo-bipolar mitosis

Question 14

Outline the process of kinetochore attachment in a functional cell

Answer 14

1. Unattached chromosome at pro-metaphase
2. 1 kinetochore binds laterally to a control MT
3. Chromosome slides towards the spindle pole
4. Lateral attachment inverts to an end-on unipolar attachment, microtubule now called kinetochore MT
5. Free kinetochore captures microtubules from opposite spindle pole to convert unipolar to bipolar attachment

Question 15

What is a syntelic chromosome attachment?

Answer 15

Some centrosomes attach to kinetochores on both sister chromatids

Question 16

What is merotelic chromosome attachment?

Answer 16

Both centrosomes have spindles which attach to the same kinetochore

Question 17

What is amphitelic chromome attachment?

Answer 17

Normal attachment

Question 18

When was aneuploidy first associated with tumours?

Answer 18

In 1890 by David Homemann and Theoder Boresi

Question 19

What is mosaic variegated aneuploidy?

Answer 19

Mutations in the BubR1 gene which causes growth retardation, microcephaly, childhood cancer and often results in early death due to premature sister chromatid seperation in >50% of lymphocytes